Substituted 5-membered ring heterocycles comprising a bicyclic or tricyclic group their preparation and their use

ABSTRACT

5-Membered ring heterocycle of the formula I,                    
     in which D includes a COOR 15 , CON(CH 3 )R 15  or CONHR 15  radical and R 15  includes a 6-24 member bicyclic or tricyclic radical, compositions, preparation and use as inhibitors of thrombocyte aggregation, metastasization of carcinoma cells, binding of osteoclasts to bone surfaces and for the treatment of tromboses.

This application is a division of application Ser. No. 08/640,895, filedJul. 19, 1996, and now U.S. Pat. No. 5,981,492.

The present invention relates to substituted 5-membered ringheterocycles, their preparation and their use as medicines, inparticular as inhibitors of blood platelet aggregation.

EP-A-449 079, EP-A-530 505, EP-A-566 919 and WO-A-93/18057 describehydantoin derivatives which exhibit thrombocyte aggregation-inhibitingeffects. EP-A 512 831 mentions pyrrolidone derivatives which prevent thebinding of fibrinogen to blood platelets and hence aggregation of theplatelets. Further investigations demonstrated that the compounds of thepresent invention are also strong inhibitors of blood plateletaggregation.

The present invention relates to 5-membered ring heterocycles of thegeneral formula I,

in which

W represents R¹-A-C(R¹³) or R¹-A-CH═C;

Y represents a carbonyl group, a thiocarbonyl group or a methylenegroup;

Z represents N(R⁰), oxygen, sulphur or a methylene group;

A denotes a divalent radical from the group (C₁-C₆)-alkylene,(C₃-C₇)-cycloalkylene, phenylene, phenylene-(C₁-C₆)-alkyl,(C₁-C₆)-alkylene-phenyl or phenylene-(C₂-C₆)-alkenyl, or a divalentradical of a 5-membered or 6-membered saturated or unsaturated ringwhich can contain 1 or 2 nitrogen atoms and can be substituted once ortwice by (C₁-C₆)-alkyl or doubly bonded oxygen or sulphur;

B denotes a divalent radical from the group (C₁-C₆)-alkylene,(C₂-C₆)-alkenylene, phenylene, phenylene-(C₁-C₃)-alkyl or(C₁-C₃)-alkylene-phenyl;

D represents C(R²) (R³), N(R³) or CH═C(R³);

E denotes tetrazolyl, (R⁸O)₂P(O), HOS(O)₂, R⁹NHS(O)₂ or R¹⁰CO;

R and R⁰ denote, independently of each other, hydrogen, (C₁-C₈)-alkyl,(C₃-C₈)-cycloalkyl, optionally substituted (C₆-C₁₄)-aryl, or(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which is optionally substituted in the arylradical;

R¹ represents X—NH—C(═NH)—(CH₂)_(p) or X¹—NH—(CH₂)_(p), where p canrepresent an integer from 0 to 3;

X denotes hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkylcarbonyl,(C₁-C₆)-alkoxycarbonyl,(C₁-C₁₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl, optionally substituted(C₆-C₁₄)-arylcarbonyl, optionally substituted (C₆-C₁₄)-aryloxycarbonyl,(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl which can also be substituted inthe aryl radical, (R⁸O)₂P(O), cyano, hydroxyl, (C₁-C₆)-alkoxy,(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxy which can also be substituted in the arylradical, or amino;

X¹ has one of the meanings of X or denotes R′—NH—C(═N—R″), where R′ andR″, independently of each other, have the meanings of X;

R² denotes hydrogen, (C₁-C₈)-alkyl, optionally substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which is optionallysubstituted in the aryl radical, or (C₃-C₈)-cycloalkyl;

R³ denotes hydrogen, (C₁-C₈)-alkyl, optionally substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which is optionallysubstituted in the aryl radical, (C₃-C₈)-cycloalkyl, (C₂-C₈)-alkenyl,(C₂-C₈)-alkynyl, (C₂-C₈)-alkenylcarbonyl, (C₂-C₈)-alkynylcarbonyl,pyridyl, R¹¹NH, R⁴CO, COOR⁴, CON(CH₃)R¹⁴, CONHR¹⁴, CSNHR¹⁴, COOR¹⁵,CON(CH₃R¹⁵ or CONHR¹⁵;

R⁴ denotes hydrogen or (C₁-C₂₈)-alkyl which can optionally besubstituted once or more than once by identical or different radicalsR^(4′);

R^(4′) denotes hydroxyl, hydroxycarbonyl, aminocarbonyl, mono- ordi-((C₁-C₁₈)-alkyl)-aminocarbonyl, amino-(C₂-C₁₈)-alkylaminocarbonyl,amino-(C₁-C₃)-alkyl-phenyl-(C₁-C₃)-alkylaminocarbonyl,(C₁-C₁₈)-alkylcarbonylamino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,(C₁-C₁₈)-alkylcarbonylamino-(C₂-C₁₈)-alkylaminocarbonyl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkoxycarbonyl which can also be substituted inthe aryl radical, amino, mercapto, (C₁-C₁₈)-alkoxy,(C₁-C₁₈)-alkoxycarbonyl, optionally substituted (C₃-C₈)-cycloalkyl,halogen, nitro, tribuloromethyl or the radical R⁵;

R⁵ denotes optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which is optionally substituted in the arylradical, a monocyclic or bicyclic 5- to 12-membered heterocyclic ringwhich can be aromatic, partially hydrogenated or completely hydrogenatedand which can contain one, two or three identical or differentheteroatoms from the group nitrogen, oxygen and sulphur, a radical R⁶ ora radical R⁶CO—, where the aryl radical and, independently thereof, theheterocycle radical can be substituted once or more than once byidentical or different radicals from the group (C₁-C₁₈)-alkyl,(C₁-C₁₈)-alkoxy, halogen, nitro, amino or trifluoromethyl;

R⁶ represents R⁷R⁸N, R⁷O or R⁷S, or denotes an amino acid side chain, anatural or unnatural amino acid radical, imino acid radical, optionallyN—(C₁-C₈)-alkylated or N—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated) azaamino acidradical or a dipeptide radical which can also be substituted in the arylradical and/or in which the peptide bond can be reduced to —N—CH₂—, andalso the esters and amides thereof, where hydrogen or hydroxymethyl canoptionally stand in place of free functional groups and/or where freefunctional groups can be protected by protective groups which arecustomary in peptide chemistry;

R⁷ denotes hydrogen, (C₁-C₁₈)-alkyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl,(C₁-C₁₈)-alkylcarbonyl, (C₁-C₁₈)-alkoxycarbonyl, (C₆-C₁₄)-arylcarbonyl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkylcarbonyl or(C₆-C₁₄)-aryl-(C₁-C₁₈)-alkoxycarbonyl, where the alkyl groups canoptionally be substituted by an amino group and/or where the arylradicals can be substituted once or more than once, preferably once, byidentical or different radicals from the group (C₁-C₈)-alkyl,(C₁-C₈)-alkoxy, halogen, nitro, amino and trifluoromethyl, a natural orunnatural amino acid radical, imino acid radical, optionallyN—(C₁-C₈)-alkylated or N—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated) azaamino acidradical or a dipeptide radical which can also be substituted in the arylradical and/or in which the peptide bond can be reduced to —NH—CH₂—;

R⁸ denotes hydrogen, (C₁-C₁₈)-alkyl, optionally substituted(C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which can also besubstituted in the aryl radical;

R⁹ denotes hydrogen, aminocarbonyl, (C₁-C₁₈)-alkylaminocarbonyl,(C₃-C₈)-cycloalkylaminocarbonyl, optionally substituted(C₆-C₁₄)-arylaminocarbonyl, (C₁-C₁₈)-alkyl, optionally substituted(C₆-C₁₄)-aryl, or (C₃-C₈)-cycloalkyl;

R¹⁰ denotes hydroxyl, (C₁-C₁₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxywhich can also be substituted in the aryl radical, optionallysubstituted (C₆-C₁₄)-aryloxy, amino or mono- ordi-((C₁-C₁₈)-alkyl)-amino;

R¹¹ denotes hydrogen, (C₁-C₁₈)-alkyl, R¹²CO, optionally substituted(C₆-C₁₄)-aryl-S(O)₂, (C₁-C₁₈)-alkyl-S(O)₂, (C₆-C₁₄)-aryl-(C₁-C₈)-alkylwhich is optionally substituted in the aryl radical, or R⁹NHS(O)₂;

R¹² denotes hydrogen, (C₁-C₁₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,optionally substituted (C₆-C₁₄)-aryl, (C₁-C₁₈)-alkoxy,(C₆-C₁₄)-aryl-(C₁-C₁₈)-alkoxy which can also be substituted in the arylradical, optionally substituted (C₆-C₁₄)-aryloxy, amino or mono- ordi-((C₁-C₁₈)-alkyl)-amino;

R¹³ denotes hydrogen, (C₁-C₆)-alkyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl whichis optionally substituted in the aryl radical, or (C₃-C₈)-cycloalkyl;

R¹⁴ denotes hydrogen or (C₁-C₂₈)-alkyl which can optionally besubstituted once or more than once by identical or different radicalsfrom the group hydroxyl, hydroxycarbonyl, aminocarbonyl, mono- ordi-((C₁-C₁₈)-alkyl)-aminocarbonyl, amino-(C₂-C₁₈)-alkylaminocarbonyl,amino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,(C₁-C₁₈)-alkylcarbonylamino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,(C₁-C₁₈)-alkylcarbonyl-amino-(C₂-C₁₈)-alkylaminocarbonyl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkoxycarbonyl which can also be substituted inthe aryl radical, amino, mercapto, (C₁-C₁₈)-alkoxy,(C₁-C₁₈)-alkoxycarbonyl, optionally substituted (C₃-C₈)-cycloalkyl,HOS(O)₂-(C₁-C₃)-alkyl, R⁹NHS(O)₂-(C₁-C₃)-alkyl,(R⁸O)₂P(O)-(C₁-C₃)-alkyl, tetrazolyl-(C₁-C₃)-alkyl, halogen, nitro,trifluoromethyl and R⁵;

R¹⁵ represents R¹⁶-(C₁-C₆)-alkyl or represents R¹⁶;

R¹⁶ represents a 6- to 24-membered bicyclic or tricyclic radical whichis saturated or partially unsaturated and which can also contain one tofour identical or different heteroatoms from the group nitrogen, oxygenand sulphur, and which can also be substituted by one or more identicalor different substituents from the group (C₁-C₄)-alkyl and oxo;

b, c, d and f, independently of each other, can represent 0 or 1, butcannot all simultaneously be 0;

e, g and h, independently of each other, can represent integers from 0to 6;

where, however, when, at the same time, W represents R¹-A-CH orR¹-A-CH═C, D represents N(R³) and c, d and f represent 0, R³ cannot thenrepresent COOR^(a) or CONHR^(b), where R^(a) represents methyl which issubstituted by a 9-fluorenyl radical and R^(b) represents methyl whichis substituted by a phenyl radical and a methoxycarbonyl group;

and where, when, at the same time, W represents R¹-A-CH or R¹-A-CH═C, Drepresents C(R²) (R³), R² represents hydrogen or phenyl, and e, f and grepresent 0, R³ cannot then represent hydrogen, COOR⁴, CONHR⁴ orCON(CH₃)R⁴ or, when Z also at the same time represents a methylenegroup, cannot represent CONHR^(c), where R⁴ represents hydrogen,unsubstituted (C₁-C₂₈)-alkyl or (C₁-C₂₈)-alkyl which is exclusivelysubstituted once or more than once by identical or different R^(4′)radicals, and R^(c) represents methyl which is substituted by a phenylradical and an aminocarbonylaminosulphonyl group;

and the physiologically tolerated salts thereof.

Cycloalkyl radicals are, in particular, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexy, cycloheptyl and cyclooctyl, which, however, canalso be substituted by, for example, (C₁-C₄)-alkyl. Examples ofsubstituted cycloalkyl radicals are 4-methylcyclohexyl and2,3-dimethylcyclopentyl. This also applies in an analogous manner forcycloalkylene radicals.

Alkyl radicals can be straight-chain or branched. This also applies whenthey carry substituents or appear as substituents of other radicals, forexample in alkoxy radicals, alkoxycarbonyl radicals or aralkyl radicals.This applies in a corresponding radicals or aralkyl radicals. Thisapplies in a corresponding manner for alkylene radicals. Examples ofsuitable C₁-C₂₈-alkyl radicals are: methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, decyl, undecyl, dodecyl, tridecyl,pentadecyl, hexadecyl, heptadecyl, nonadecyl, eicosyl, docosyl,tricosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, isopropyl,isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,3,5-trimethylhexyl,sec-butyl, tert-butyl and tert-pentyl. Preferred alkyl radicals aremethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl andtert-butyl. Examples of alkylene radicals are methylene, ehtylene,trimethylene, tetramethylene, pentamethylene and hexamethylene.

Alkenyl radicals and alkenylene radicals, and also alkynyl radicals, canalso be straight-chain and branched. Examples of alkenyl radicals arevinyl, 1-propenyl, allyl, butenyl and 3-methyl-2-butenyl, of alkenyleneradicals, vinylene or propenylene, and of alkynyl radicals, ethynyl,1-propynyl or propargyl.

The 6- to 24-membered bicyclic and tricyclic radicals representing R¹⁶are obtained formally by abstracting a hydrogen atom from bicycles ortricycles, respectively. While the underlying bicycles and tricycles cancontain only carbon atoms as ring members, and can thus bebicycloalkanes and tricycloalkanes, they can also contain 1 to 4identical or different heteroatoms from the group nitrogen, oxygen andsulphur and can thus be aza-, oxa- and thia-bicycloalkanes and aza-,oxa- and thia-tricycloalkanes. If heteroatoms are contained, one or twoheteroatoms, in particular nitrogen atoms or oxygen atoms, are thenpreferably contained. The heteroatoms can occupy any positions in thebicyclic or tircyclic skeleton; they can be located in the bridges or,in the case of the nitrogen atoms, also at the bridgeheads. Both thebicycloalkanes and tricycloalkanes and also their hetero analogues canbe completely saturated or contain one or more double bonds; preferably,they contain one or two double bonds or are, in particular, completelysaturated. Both the bicycloalkanes and tricycloalkanes and also thehetero analogues, and both the saturated and the unsaturatedrepresentatives, can be unsubstituted or be substituted in any suitablepositions by one or more oxo groups and/or one or more identical ordifferent (C₁-C₄)-alkyl groups, e.g. methyl groups or isopropyl groups,preferably methyl groups. The free bond of the bicyclic or tricyclicradical can be located in any position in the molecule; the radical canthus be bonded via a bridgehead atom or an atom in a bridge. The freebond can also be located in any stereo-chemical position, for example inan exo position or an endo position.

Examples of parent substances of bicyclic ring systems, from which abicyclic radical representing R¹⁶ can be derived, are norbornane(=bicyclo[2.2.1]heptane), bicyclo[2.2.2]octane and bicyclo[3.2.1]octane;examples of unsaturated or substituted systems containing heteroatomsare 7-azabicyclo[2.2.1]heptane, bicyclo[2.2.2]oct-lene and camphor(=1,7,7-trimethyl-2-oxobicyclo[2.2.1]heptane).

Examples of systems from which a tricyclic radical representing R¹⁶ canbe derived are twistane (=tricyclo[4.4.0.0^(3,8)]-decane), adamantane(=tricyclo[3.3.1.1^(3,7)]decane), noradamantane(=tricyclo[3.3.1.0^(3,7)]nonane), tricyclo[2.2.1.0^(2,6)]heptane,tricyclo[5.3.2.0^(4,9)]dodecane, tricylco[5.4.0.0^(2,9)]undecane ortricylco[5.5.1.0^(3,11)]tridecane.

Preferably, bicyclic or tricyclic radicals representing R¹⁶ are derivedfrom bridged bicycles or tricycles, that is from systems in which ringshave two or more than two atoms in common. In addition to this,preference is also given to bicyclic and tricyclic radicals having from6 to 18 ring members, particularly preferably to those have from 7 to 12ring members.

Specific bicyclic and tricyclic radicals which are particularlypreferred are the 2-norbornyl radical, both that with the free bond inthe exo position and that with the free bond in the endo position, the2-bicyclo[3.2.1]octyl radical, the 1-adamantyl radical, the 2-adamantylradical and the 3-noradamantyl radical. Apart from this, preferredradicals are the 1-adamantyl and 2-adamantyl radicals.

Examples of (C₆-C₁₄)-aryl groups are phenyl, naphthyl, biphenylyl orfluorenyl, with 1-naphthyl, 2-naphythyl and, in particular, phenyl beingpreferred. Aryl radicals, in particular phenyl radicals, can besubstituted once or more than once, preferably once, twice or threetimes, by identical or different radicals form the group (C₁-C₈)-alkyl,in particular (C₁-C₄)-alkyl, (C₁-C₈)-alkoxy, in particular(C₁-C₄)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl,methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl,(C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benxyloxy, (R⁸O)₂P(O),(R⁸O)₂P(O)—O— and tetrazolyl. This applies in a corresponding manner,for example, for radicals such as aralkyl or arylcarbonyl. Aralkylradicals are, in particular, benzyl and also 1- and 2-naphthylmethyl and9-fluorenylmethyl, which radicals can also be substituted. Examples ofsubstituted aralkyl radicals are halobenzyl or (C₁-C₄)-alkoxybenzyl.Examples of pyridyl are 2-pyridyl, 3-pyridyl and 4-pyridyl.

In monosubstituted phenyl radicals, the substituent can be located inthe 2, the 3 or the 4 position, with the 3 and 4 positions beingpreferred. If phenyl is substituted twice, the substituents can be inthe 1,2 positions, 1,3-positions or 1,4 positions in relation to eachother. In phenyl radicals which have been substituted twice, the twosubstituents are preferably arranged in the 3 and 4 positions, based onthe linkage site. This applies in a corresponding manner for phenyleneradicals.

Phenylene-(C₁-C₆)-alkyl is, in particular, phenylenemethyl andphenyleneethyl. Phenylene-(C₂-C₆)-alkenyl is, in particular,phenyleneethenyl and phenylenepropenyl.

Examples of monocyclic or bicyclic 5- to 12-membered heterocyclic ringsare pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl,pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quniolyl,isoquinolyl, uninoxalinyl, quinazolinyl, cinnolinyl or a benzo-fused,cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivative ofthese radicals.

These heterocycles can be substituted at a nitrogen atom by(C₁-C₇)-alkyl, e.g. methyl or ethyl, phenyl or phenyl-(C₁-C₄)-alkyl,e.g. benzyl, and/or at one or more carbon atoms by (C₁-C₄)-alkyl,halogen, hydroxyl, (C₁-C₄)-alkoxy, e.g. methoxy, phenyl-(C₁-C₄)-alkoxy,e.g. benzyloxy, or oxo, and be aromatic or partially or completelysaturated. Nitrogen heterocycles can also be present as N-oxides.

Examples of radicals of this nature are 2- or 3-pyrrolyl,phenyl-pyrrolyl, e.g. 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl,4-imidazolyl, methyl-imidazolyl, e.g. 1-methyl-2-, 4- or 5-imidazolyl,1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridyl-N-oxide,2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted2-indolyl, e.g. 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-,5-chloro- or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or 3-indolyl,4,5,6,7-tetrahydro-2-indolyl, cyclohepta[b]-5-pyrrolyl, 2-, 3- or4-quniolyl, 1-, 3- or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquniolyl,2-qunioxalinyl, 2-benzofuranyl, 2-benzothienyl, 2-benzoxazolyl orbenzothiazolyl. Examples of partially hydrogenated or completelyhydrogenated heterocyclic rings are dihydropyridinyl, pyrrolidinyl, e.g.2-, 3- or 4-(N-methylpyrrolidinyl), piperazinyl, morpholinyl,thiomorpholinyl, tetrahydrothienyl and benzodioxolanyl.

Halogen represents fluorine, chlorine, bromine or iodine, in particularfluorine or chlorine.

Natural and unnatural amino acids can, if chiral, be present in the Dform or L form. Preference is given to α-amino acids. The following maybe mentioned by way of example (cf. Houben-Weyl, Methoden derorganischen Chemie (Methods of organic chemistry), Volume XV/1 and 2,Stuttgart, 1974):

Aad, Abu, γAbu, ABz, 2ABz, εAca, Ach, Acp, Adpd, Ahb, Aib, βAib, Ala,βAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze,Azi, Bai, Bph, Can, Cit, Cys, (Cys)₂, Cyta, Daad, Dab, Dadd, Dap, Dapm,Dasu, Djen, Dpa, Dtc, Fel, Gln, Flu, Gly, Guv, hAla, hArg, hCys, hGln,hGlu, His, hIle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr,Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, βLys,ΔLys, Met, Min, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg,Pic, Pro, ΔPro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi,βThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, Tbg, Npg, Chg,Cha, Thia, 2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenylaminoaceticacid and 2-(p-chlorophenyl)aminoacetic acid.

Amino acid side chains are understood to mean side chains of natural orunnatural amino acids. Azaamino acids are natural or unnatural aminoacids in which the central structural component

Radicals of heterocycles from the following group are particularlysuitable as the radical of an imino acid:

pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid;tetrahydroisoquinoline-3-carboxylic acid;decahydroisoqunioline-3-carboxylic acid; octahydroindole-2-carboxylicacid, decahydroqunioline-2-carboxylic acid,octahydrocyclopenta[b]pyrrole-2-carboxylic acid;2-azabicyclo[2.2.2]octane-3-carboxylic acid;2-azabicylco[2.2.1]heptane-3-carboxylic acid;2-azabicyclo[3.1.0]-hexane-3-carboxylic acid;2-azaspiro[4.4]nonane-3-carboxylic acid;2-azaspiro[4.5]decane-3-carboxylic acid;spiro(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid;sprio(bicyclo-[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid;2-azatricyclo-[4.3.0.1^(6,9)]decane-3-carboxylic acid;decahydrocyclohepta[b]-pyrrole-2-carboxylic acid;decahydrocycloocta[c]pyrrole-2-carboxylic acid;octehydrocyclopenta[c]pyrrole-2-carboxylic acid;octahydroisoindole-1-carboxylic acid;2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid;2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid;tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid;pyrazolidine-3-carboxylic acid and hydroxypyrrolidine-2-carboxylic acid;which may all optionally be substituted (see the following formulae):

The heterocycles underlying the above mentioned radicals are known, forexample, from

U.S. Pat. No. 4,344,949; U.S. Pat. No. 4,374,847; U.S. Pat. No.4,350,704; EP-A 29,488; EP-A 31,741; EP-A 46,953; EP-A 49,605; EP-A49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164;EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109,020; EP-A111,873; EP-A 271,865 and EP-A 344,682.

Dipeptides can contain natural or unnatural amino acids, imino acids andalso azaamino acids as structural components. Furthermore, the naturalor unnatural amino acids, imino acids, azaamino acids and dipeptides canalso be present as esters or amides, such as, for example, methyl ester,ethyl ester, isopropyl ester, isobutyl ester, tert-butyl ester, benzylester, ethyl amide, semicarbazide or ω-amino-(C₂-C₈)-alkyl amide.

Functional groups of the amino acids, imino acids and dipeptides can bepresent in protected form. Suitable protective groups, such as, forexample, urethane protective groups, carboxyl protective groups andside-chain protective groups, are described in Hubbuch, Kontakte(Contacts) (Merck) 1979, No. 3, pp. 14 to 23 and in Büllesbach, Kontakte(Contacts) (Merck) 1980, No. 1, pp. 23 to 35. Those which be mentionedin particular are: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc,Msc, Moc, Z(NO₂), Z(Hal_(n)), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl,OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.

Physiologically tolerated salts of the compounds of the general formulaI are, in particular, pharmaceutically utilizable or non-toxic salts.

Such salts are formed, for example, from compounds of the generalformula I which contain acidic groups, e.g. carboxyl, using alkalimetals or alkaline earth metals, such as, for example, Na, K, Mg and Ca,and also using physiologically tolerated rated organic amines, such as,for example, triethylamine, ethanolamine or tris(2-hydroxyethyl)amine.

Compounds of the general formula I which contain basic groups, forexample an amino group, an amidino group or a guanidino group, formsalts with inorganic acids, such as, for example, hydrochloric acid,sulphuric acid or phosphoric acid, and with organic carboxylic orsulphonic acids, such as, for example, acetic acid, citric acid, benzoicacid, maleic acid, fumaric acid, tartaric acid, methanesulphonic acid orp-toluenesulphonic acid.

The compounds of the general formula I according to the invention cancontain optically active carbon atoms which, independently of eachother, can have the R or the S configuration, and consequently bepresent in the form of pure enantiomers or pure diastereomers or in theform of enantiomeric mixtures or diastereomeric mixtures. Both pureenantiomers and enantiomeric mixtures and also diastereomers anddiastereomeric mixtures are subject-matter of the present invention.

In addition to this, the compounds of the general formula I according tothe invention can contain mobile hydrogen atoms and consequently bepresent in different tautomeric forms. These tautomers are also thesubject-matter of the present invention.

When W represents R¹—A—C(R¹³), A preferably represents methylene,ethylene, trimethylene, tetramethylene, cyclohexylene, phenylene,phenylenemethyl or phenyleneethenyl; when W represents R¹—A—CH═C, Apreferably represents phenylene.

Y preferably represents a carbonyl group; Z preferably represents N(R⁰).

B preferably represents methylene, ethylene, trimethylene,tetramethylene, vinylene or phenylene.

D preferably represents C(R²)(R³) or N(R³).

E preferably represents R⁹NHS(O)₂ or R¹⁰CO.

R and R⁰ preferably represent, independently of each other, hydrogen,(C₁-C₆)-alkyl or benzyl.

R¹ preferably represents X—NH—C(═NH), X—NH—C(═NX)—NH or X—NH—CH₂.

X and X¹ preferably represent hydrogen, (C₁-C₆)-alkylcarbonyl,(C₁-C₆)-alkoxycarbonyl or(C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl or(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl, with X¹ additionally representingR¹—NH—C(═NR″), where R′ and R″, independently of each other, have thepreferred meanings of X.

R² preferably represents hydrogen or (C₁-C₈)-alkyl.

R³ preferably represents (C₁-C₈)-alkyl, optionally substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl,(C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, pyridyl, R¹¹NH, R⁴CO, COOR⁴, CONHR¹⁴,CSNHR¹⁴, COOR¹⁵ or CONHR¹⁵.

R¹³ preferably represents hydrogen and, in particular, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl or benzyl, where a very particularly preferred alkylradical which R¹³ represents is the methyl radical.

R¹⁵ preferably represents R¹⁶-(C₁-C₃)-alkyl or represents R¹⁶, andparticularly preferably represents R¹⁶-(C₁)-alkyl or R¹⁶. In addition tothis, when R³ represents COOR¹⁵, R¹⁵ preferably represents theexo-2-norbornyl radical, the endo-2-norbornyl radical or the2-bicyclo[3.2.1]octyl radical, and, when R³ represents CONHR¹⁵, R¹⁵preferably represents the exo-2-norbornyl radical, the endo-2-norbornylradical, the 3-noradamantyl radical, and, in particular, the 1-adamantylradical, the 2-adamantyl radical, the 1-adamantyl radical or the2-adamantylmethyl radical.

R¹⁶ preferably represents a 7- to 12-membered bridged bicyclic ortricyclic radical which is saturated or partially unsaturated and whichalso can contain one to four identical or different heteroatoms from thegroup nitrogen, oxygen and sulphur and which also can be substituted byone or more identical or different substituents from the group(C₁-C₄)-alkyl and Oxo;

b, c and d preferably represent, independently of each other, 1,

e, g and h preferably represent, independently of each other, integersfrom 0 to 3.

Preferred compounds of the general formula I are those in which

W represents R¹—A—CH═C and in this A represents a phenylene radical, orW represents R¹—A—C(R¹³) and in this A represents a divalent radicalfrom the group methylene, ethylene, trimethylene, tetramethylene,cyclohexylene, phenylene or phenylenemethyl;

B represents a divalent radical from the group methylene, ethylene,trimethylene, tetramethylene, vinylene or phenylene;

E denotes R⁹NHS(O)₂ or R¹⁰CO;

R and R⁰ denote, independently of each other, hydrogen, (C₁-C₆)-alkyl orbenzyl;

R¹ represents X—NH—C(═NH), X—NH—C(═NX)—NH or X—NH—CH₂;

X represents hydrogen, (C₁-C₆)-alkylcarbonyl, (C₁-C₆)-alkoxycarbonyl,(C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl or(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl;

R² represents hydrogen or (C₁-C₈)-alkyl;

R³ represents (C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, (C₂-C₈)-alkenyl,(C₂-C₈)-alkynyl, pyridyl, R¹¹NH, R⁴CO, COOR⁴, CONHR¹⁴, CSNHR¹⁴, COOR¹⁵and CONHR¹⁵; and

e, g and h, represents of each other, represent integers from 0 to 3.

Particularly preferred compounds of the general formula I are those inwhich R³ represents optionally substituted (C₆-C₁₄)-aryl, representsCOOR⁴, represent R¹¹NH or represent CONHR¹⁴, where —NHR¹⁴ represents theradical of an α-amino acid, its ω-amino-(C₂-C₈)-alkyl amide or its(C₁-C₈)-alkyl ester or its (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl ester. In thiscontext, the radical of an α-amino acid representing —NHR¹⁴ is obtainedformally by abstracting a hydrogen atom from the amino group of theamino acid. Among these compounds, those which are very particularlypreferred are compounds of the general formula I in which R³ representsCONHR¹⁴, where —NHR¹⁴ represents the radical of the α-amino acidsvaline, lysine, phenylglycine, phenylalanine or tryptophan, or their(C₁-C₈)-alkyl esters or (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl esters.

Compounds which are preferred in addition to this are those of thegeneral formula I in which, at the same time,

W represents R¹—A—C(R¹³);

Y represents a carbonyl group;

Z represents N(R⁰);

A represents a 1,4-phenylene radical;

B represents a methylene radical;

D represents C(R²)(R³);

E represents R¹⁰CO;

R and R⁰, independently of each other, represent hydrogen or(C₁-C₄)-alkyl, in particular hydrogen, methyl or ethyl;

R¹ represents H₂N—C(═NH), H₂N—C(═NH) or H₂N—CH₂;

R² represents hydrogen;

R³ represents the radical CONHR¹⁴;

R¹⁰ represents hydroxyl or (C₁-C₈)-alkoxy, preferably (C₁-C₄)-alkoxy;

R¹³ represents (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or benzyl, inparticular methyl;

R¹⁴ represents methyl which is substituted by phenyl or hydroxycarbonyl,or represents methyl which is substituted by phenyl and(C₁-C₈)-alkoxycarbonyl, preferably (C₁-C₄)-alkoxycarbonyl;

b, c and d represent 1 and e, f and g represent 0;

h represents 1 or 2, and preferably represents 1.

If —NHR¹⁴ represents a (C₁-C₈)-alkyl ester of an α-amino acid, or if R¹⁴contains an alkoxycarbonyl radical, the methyl, ethyl, isopropyl,isobutyl or tert-butyl ester is then preferred; if —NHR¹⁴ represents a(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl ester of an α-amino acid, the benzyl esteris then preferred.

Particularly preferred compounds of the general formula I arefurthermore those in which

W represents R¹—A—CH═C and in this A represents a phenylene radical, orW represents R¹—A—C(R¹³) and in this A represents a divalent radicalfrom the group methylene, ethylene, trimethylene, tetramethylene,cyclohexylene, phenylene or phenylenemethyl;

B represents a divalent radical from the group methylene, ethylene,trimethylene, tetramethylene, vinylene or phenylene;

E denotes N¹⁰CO;

R and R⁰ denote, independently of each other, hydrogen or (C₁-C₆)-alkyl;

R¹ represents X—NH—C(═NH), X—NH—C(═NX)—NH or X—NH—CH₂;

X represents hydrogen, (C₁-C₆)-alkylcarbonyl, (C₁-C₆)-alkoxycarbonyl,(C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl or(C₆-C₆)-aryl-(C₁-C₆)-alkoxycarbonyl;

R² represents hydrogen or (C₁-C₈)-alkyl;

R³ represents CONHR¹⁵;

R¹⁵ represents R¹⁶-(C₁-C₆)-alkyl or R¹⁶, where R¹⁶ represents a 7- to12-membered bridged bicyclic or tricyclic radical which is saturated orpartially unsaturated and which can also contain one to four identicalor different heteroatoms from the group nitrogen, oxygen and sulphur andwhich can also be substituted by one or more identical or differentsubstituents from the group (C₁-C₄)-alkyl and oxo, and, in particular,R¹⁵ represents an adamantyl radical or an adamantylmethyl radical;

and e, g and h, independently of each other, represent integers from 0to 3, and b, c and d represent 1.

Among these particularly preferred compounds of the general formula I,containing a bicyclic or tricyclic radical representing R¹⁶, those arevery particularly preferred in which, at the same time,

W represents R¹—A—C(R¹³);

Y represents a carbonyl group;

Z represents N(R⁰);

A represents a 1,4-phenylene radical;

B represents a methylene radical;

D represents C(R²)(R³);

E represents R¹⁰CO;

R and R⁰, independently of each other, represent hydrogen or(C₁-C₄)-alkyl, in particular hydrogen, methyl or ethyl;

R¹ represents H₂N—C(═NH), H₂N—C(═NH)—NH or H₂N—CH₂;

R² represents hydrogen;

R³ represents the radical CONHR¹⁵;

R¹⁰ represents hydroxyl or (C₁-C₈)-alkoxy, preferably (C₁-C₄)-alkoxy;

R¹³ represents (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or benzyl, inparticular methyl;

R¹⁵ represents an adamantyl radical or an adamantylmethyl radical;

b, c and d represent 1 and e, f and g represent 0;

h represents 1 or 2, and preferably represents 1.

Furthermore, particularly preferred compounds of the general formula Iare also those in which, at the same time,

W represents R¹—A—C(R¹³);

Y represents a carbonyl group;

Z represents N(R⁰);

A represents a 1,4-phenylene radical;

B represents a methylene radical;

D represents C(R²)(R³);

E represents R¹⁰CO;

R and R⁰, independently of each other, represent hydrogen or(C₁-C₄)-alkyl, in particular hydrogen, methyl or ethyl;

R¹ represents H₂N—C(═NH), H₂N—C(═NH)—NH or H₂N—CH₂;

R² represents hydrogen;

R³ represents an unsubstituted phenyl radical or naphthyl radical, aphenyl radical or naphthyl radical which is substituted by one, two orthree identical or different radicals from the group (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, hydroxyl, halogen, triflouromethyl, nitro,methylenedioxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, aminocarbonyl,cyano, phenyl, phenoxy and benzyloxy, a pyridyl radical, a (C₁-C₄)-alkylradical, a (C₂-C₄)-alkenyl radical, a (C₂-C₄)-alkynyl radical or a(C₅-C₆)-cycloalkyl radical, and, in particular R³ represents a phenylradical;

R¹⁰ represents hydroxyl or (C₁-C₈)-alkoxy, in particular preferably(C₁-C₄)-alkoxy, and, preferably R¹⁰ represents a radical from the grouphydroxyl, methoxy, ethoxy, propoxy and isopropoxy;

R¹³ represents (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or benzyl, inparticular methyl;

b, c and d represent 1 and e, f and g represent 0;

h represents 1 or 2; and preferably represents 1.

Among these particularly preferred compounds of the general formula Ithose are very particularly preferred in which, at the same time,

W represents R¹—A—C(CH₃);

Y represents a carbonyl group;

Z represents NH;

A represents a 1,4-phenylene radical;

R¹ represents an amino-imino-methyl radical;

B represents a methylene radical;

D represents CH(phenyl);

E represents hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl orisopropoxycarbonyl;

R represents hydrogen;

b, c, d and h represent 1, and e, f and g represent 0.

Of these very particularly preferred compounds, those are preferred overand above this which in each case have a uniform configuration at thechiral centre in the 4 position of the imidazolidine ring and the chiralcarbon atom representing D, and in particular have the S configurationat the carbon atom representing D.

Also, in all the preferred embodiments, the present invention naturallyembraces, as has already been mentioned above, the physiologicallytolerated salts of the compounds.

Compounds of the formula I can be prepared, for example, by fragmentcondensation of a compound of the general formula II

with a compound of the general formula III,

in which W, Y, Z, B, D, E and R, and also b, d, e, f, g and h, aredefined as indicated above, and G represents hydroxycarbonyl,(C₁-C₆)-alkoxycarbonyl, activated carboxylic acid derivatives, such asacid chlorides active esters or mixed anhydrides, or representsisocyanato.

In order to condense the compounds of the general formula II with thoseof the general formula III, use in advantageously made of the couplingmethods of peptide chemistry which are known per se (see, for example,Houben-Weyl, Methoden der Organischen Chemie, (Methods of organicchemistry), Volumes 15/1 and 15/2, Stuttgart, 1974). For this purpose,it is necessary, as a rule, for non-reacting amino groups which arepresent to be protected during the condensation by reversible protectivegroups. This is also the case for the carboxyl groups of the compoundsof the formula III, which are preferably present as (C₁-C₆)-alkylesters, benzyl esters or tert-butyl esters. An amino-group protection isnot necessary when the amino groups to be generated are still present asnitro groups or cyano groups and are only formed by hydrogenation afterthe coupling. After the coupling, the protective groups which arepresent are eliminated in a suitable manner. For example, NO₂ groups(guanidino protection), benzyloxycarbonyl groups and benzyl esters canbe removed by hydrogenation. The protective groups of the tert-butyltype are cleaved acidically, while the 9-fluorenylmethyloxycarbonylradical is removed by secondary amines.

The compounds of the general formula I, in which the 5-membered ringhetercycle represents a dioxo- or thioxo-oxo-substituted imidazolidinering, in which W represents R¹—A—C(R¹³), may also be obtained asfollows:

By reacting α-amino acids or N-substituted α-amino acids, or,preferably, their esters, e.g. the methyl, ethyl, tert-butyl or benzylester, for example a compound of the general formula IV,

in which R⁰, R¹, R¹³ and A are defined as indicated above, with anisocyanate or isothiocyanate, for example of the general formula V,

in which B, D, E and R, and also b, c, d, e, f, g and h, are defined asindicated above, and U denotes isocyanato, isothiocyanato ortrichloromethylcarbonylamino, urea derivatives or thiourea derivatives,for example of the general formula VI,

for which the abovementioned definitions apply, and in which V denotesoxygen or sulphur, are obtained, which derivatives are cyclized byheating with acid, with hydrolysis of the ester functions, to yieldcompounds of the general formula Ia

in which V denotes oxygen or sulphur and W represents R¹—A—C(R¹³), andfor which the abovementioned definitions otherwise apply.

During the cyclization, guanidino groups can be blocked by protectivegroups, such as NO₂ or Mtr. Amino groups in the side chain can likewisebe present in protected form (for example as Boc or Z derivatives) orstill be present as a NO₂ or cyano function which can subsequently bereduced to the amino group or, in the case of the cyano group, also beconverted into the amidino group.

Another method of preparing compounds of the general formula Ia, inwhich V denotes oxygen or sulphur and W represents R¹—A—C(R¹³), and forwhich the abovementioned definitions otherwise apply, is the reaction ofcompounds of the general formula VII.

in which W represents R¹—A—C(R¹³), and for which the abovementioneddefinitions otherwise apply, with phosgene, thiophosgene orcorresponding equivalents (in analogy with S. Goldschmidt and M. Wick,Liebigs Ann. Chem. 575 (1952), 217-231, and C. Tropp, Chem. Ber. 61(1928), 1431-1439).

The following reagents can be used for the guanylation andnitroguanylation of the amino function:

1. O-Methylisourea (S. Weiss and H. Krommer, Chemiker-Zeitung 98 (1974)617-618),

2. S-Methylisothiourea R. F. Borne, M. L. Forrester and I. W. Waters, J.Med. Chem. 20 (1977) 771-776),

3. Nitro-S-methylisothiourea (L. S. Hafner and R. E. Evans, J. Org.Chem. 24 (1959) 1157),

4. Formamidinesulphonic acid (K. Kim, Y.-T. Lin and H. S. Mosher,Tetrahedron Lett. 29 (1988) 3183-3186),

5. 3,5-Dimethyl-1-pyrazolylformamidinium nitrate (F. L. Scott, D. G.O'Donovan and J. Reilly, J. Amer. Chem. Soc. 75 (1953) 4053-4054),

6. N,N′-Di-tert-butyloxycarbonyl-S-methylisothiourea (R. J. Bergeron andJ. S. McManis, J. Org. Chem. 52 (1987) 1700-1703),

7. N-Alkoxycarbonyl-, N,N′-dialkoxycarbonyl-, N-alkylcarbonyl- andN,N′-dialkylcarbonyl-S-methylisothiourea (H. Wollweber, H. Kölling, E.Niemers, A. Widding, P. Andrews, H.-P. Schulz and H. Thomas, Arzneim.Forsch./Drug Res. 34 (1984) 531-542).

Amidines can be prepared from the corresponding cyano compounds byadding on alcohols (e.g. methanol or ethanol) in acidic, anhydrousmedium (e.g. dioxane, methanol or ethanol) and subsequent aminolysis,e.g. by treating with ammonia in alcohols such as, for example,isopropanol, ethanol or methanol (G. Wagner, P. Richter and Ch. Garbe,Pharmazie 29 (1974) 12-15). Another method of preparing amidines is toadd H₂S onto the cyano group, followed by a methylation of the resultingthioamide and subsequent reaction with ammonia (GDR patent No. 235 866).

The compounds of the general formula I, and their physiologicallytolerated salts, can be administered to animals, preferably mammals,and, in particular, humans, as medicines on their own, in mixtures witheach other, or in the form of pharmaceutical preparations which permitenteral or parenteral use and which contain, as the active constituent,an effective dose of at least one compound of the general formula I, ora salt thereof, in addition to customary pharmaceutically acceptableexcipients and additives. The preparations normally contain from about0.5 to 90% by weight of the therapeutically active compound.

The medicines can be administered orally, for example in the form ofpills, tablets, lacquered tablets, coated tablets, granules, hard andsoft gelatine capsules, solutions, syrups, emulsions or suspensions, oraerosol mixtures. However, the administration can also be effectedrectally, e.g. in the form of suppositories, or parenterally, e.g. inthe form of injection solutions or infusion solutions, microcapsules orrods, or percutaneously, e.g. in the form of ointments or tinctures, ornasally, e.g. in the form of nasal sprays.

The pharmaceutical preparations are produced in a manner known per se,with pharmaceutically inert inorganic or organic excipients being used.For example, lactose, corn starch, or derivatives thereof, talc, stearicacid or its salts, etc., can be used for producing pills, tablets,coated tablets and hard gelatine capsules. Examples of excipients forsoft gelatine capsules and suppositories are fats, waxes, semi-solid andliquid polyols, natural or hardened oils, etc. Suitable excipients forpreparing solutions and syrups are, for example, water, sucrose, invertsugar, glucose, polyols, etc. Suitable excipients for producinginjection solutions are water, alcohols, glycerol, polyols, vegetableoils, etc. Suitable excipients for microcapsules, implants or rods aremixed polymers of glycolic acid and lactic acid.

In addition to the active compounds and excipients, the pharmaceuticalpreparations can also contain additives, such as, for example, fillers,extenders, disintegrants, binding agents, glidants, wetting agents,stabilizers, emulsifiers, preservatives, sweeteners, colorants,flavorants or aromatizing agents, thickeners, diluents or bufferingsubstances, and, additionally, solvents or solubilizers or agents forachieving a depot effect, and also salts for altering the osmoticpressure, coating agents or antioxidants. They can also contain two ormore compounds of the general formula I or their pharmacologicallyacceptable salts and one or more different therapeutically activecompounds in addition.

Examples of different therapeutically active substances of this natureare blood flow-promoting agents, such as dihydro-ergocristine,nicergoline, buphenine, nicotinic acid and its esters, pyridylcarbinol,bencyclane, cinnarizine, naftidrofuryl, raubasine and vincamine;positively inotropic compounds, such as digoxin, acetyldigoxin,metildigoxin and lanato-glycosides; coronary dilating agents, such ascarbocromen; dipyridamole, nifedipine and perhexiline; anti-anginouscompounds, such as isosorbide dinitrate, isosorbide mononitrate,glycerol nitrate, molsidomine and verapamil; β-blockers, such aspropranolol, oxprenolol, atenolol, metroprolol and penbutolol. Inaddition to this, the compounds can also, for example, be combined withnootropically active substances, such as, for example, piracetam, orsubstances with CNS activity, such as pirlindole, sulpiride, etc.

The dose can be varied within wide limits and must be adjusted to theindividual circumstances in each specific case. In general, a daily doseof from about 0.1 to 1 mg/kg, preferably of from 0.3 to 0.5 mg/kg, ofbodyweight is appropriate for achieving effective results in the case oforal administration, and, in the case of intravenous administration thedaily dose is, in general, from about 0.01 to 0.3 mg/kg, preferably from0.05 to 0.1 mg/kg, of bodyweight. Particularly when relatively largequantities are being administered, the daily dose can be sub-dividedinto several, e.g. 2, 3 or 4, smaller doses which are administeredseparately. Where appropriate, it can be necessary, depending on theindividual response, to deviate upwards or downwards from the daily doseindicated. Normally, pharmaceutical preparations contain from 0.2 to 50mg, preferably from 0.5 to 10 mg, of active compound of the generalformula I, or of one of its pharmaceutically acceptable salts, per dose.

The compounds of the general formula I according to the invention havethe ability to inhibit the cell/cell adhesion which is based on theinteraction of Arg-Gly-Asp-containing proteins, such as fibronectin,fibrinogen or the von Willebrand factor, with the so-called integrins.Integrins are transmembrane glycoproteins, receptors forArg-Gly-Asp-containing proteins (E. Ruoslahti and M. D. Pierschbacher,Science 238 (1987) 491-497; D. R. Phillips, I. F. Charo, L. V. Pariseand L. A. Fitzgerald, Blood 71 (1988) 831-843). In addition, theyinhibit the binding of other adhesive proteins such as vitronectin,collagen and laminin to the corresponding receptors on the surface ofdifferent cell types.

The compounds of the general formule I according to the inventioninhibit thrombocyte aggregation, the metastasization of carcinoma cellsand also the binding of osteoclasts to bone surfaces.

The compounds of the general formula I are used acutely when there isdanger of thrombosis and chronically in the prevention ofarteriosclerosis and thrombosis, e.g. in the therapy and prophylaxis ofarterial blood vessel diseases, as in acute myocardial infarction,secondary prevention of myocardial infarction, reocclusion prophylaxisfollowing lysis and dilatation (PTCA), unstable angina pectoris,transitory ischaemic attacks, stroke, coronary bypass operationsincluding reocclusion prophylaxis in association with bypass, pulmonaryembolism, peripheral occlusive arterial disease and dissecting aneurism;in the therapy of venous and microcirculatory blood vessel diseases,such as deep vein thrombosis, disseminated intravascular coagulation,post-operative and post-partum trauma, surgical or infectious shock, orsepticaemia, or in diseases with hyperreactive thrombocytes, thromboticthrombocytopenic purpura, preeclampsia, premenstrual syndrome, dialysisor extracorporeal circulation; a further application is in the treatmentof cancer, e.g. during cancer operations and also prophylactically inassociation with cancer. Furthermore, osteoporosis can be prevented byinhibiting the binding of osteoclasts to the bone surface.

The compounds are tested, in particular, for their inhibitory effect inblood platelet aggregation and the attachment of fibrinogen to bloodplatelets (use is made of gel-filtered blood platelets from human donorblood which are activated with ADP or thrombin), and also for theirin-vivo effect in inhibiting thrombocyte aggregation and thrombosis.

Test method 1

As a functional test, measurement is made of the inhibition of theaggregation of gel-filtered human thrombocytes, following stimulationwith ADP or thrombin, by the compounds according to the invention. Thevalue given is the IC₅₀ value of the inhibition [Literature: Marguerie,G. A. et al., J. Biol. Chem. 254, 5357-5363 (1979); Marguerie, G. A. etal., J. Biol. Chem. 255, 154-161 (1980)].

For this purpose, human thrombocytes were isolated from platelet-richplasma (PRP) by gel filtration on Sepharose 2 B. The resultingsuspension of gel-filtered platelets (GFP), which contained 3×10⁸platelets/ml, was activated in the presence of 1 mg/ml of fibrinogeneither with 10 μM ADP or with 0.1 U/ml thrombin, and stirred in anaggregometer (PAP 4, Biodata, Hatboro, Penna., USA) at 37° C. and at1000 revolutions per minute. The maximum increase in the translucency istaken as a measure of the aggregation. The test substances were added tothe GFP at 37° C. and 2 min before activating with ADP or thrombin. Theinhibition of the aggregation is given as an IC₅₀ value, i.e. as theaverage concentration of test substance which is required in order toelicit a 50% inhibition in GFP samples from 2-4 different donors(semilogarithmic dose/effect relationship).

In this test, the following results were obtained for the compounds ofthe examples below:

ADP-stimulated Thrombin-stimulated Example IC₅₀ (μM) IC₅₀ (μM)  1 0.040.05  6 2.5 0.8  7 0.3 0.3  8 0.15 0.1  9 1.0 0.5 10 0.15 0.06 13 0.20.2 20 2.0 1.0 21 0.8 0.5 22 0.025 0.05 23 0.03 0.05 24 0.055 0.08 250.03 0.05 26 0.02 0.04 27 0.025 0.04 28 0.025 0.04 29 0.05 0.04 30 0.50.4 31 3 0.6 32 0.2 0.15 33 0.5 0.2 34 2.5 1.5 35 0.1 0.3 36 0.2 0.15 370.1 0.2 38 0.3 0.35 39 0.08 0.15 40 0.4 0.25 41 0.1 0.15 42 0.3 0.2 430.5 0.5 44 0.4 0.2 45 0.2 0.2 46 0.1 0.1 47 0.1 0.15 48 2.0 0.8 49 0.60.2 50 0.55 0.4 52 0.5 0.4 56 0.1 0.06 57 6 5 58 0.02 0.025 59 50 40 605 4 67 0.08 0.2 68 0.05 0.045 69 0.025 0.045 70 0.065 0.07

Test method 2

The inhibition of the binding of fibrinogen to its receptor(glycoprotein IIb/IIIa) by the compounds according to the invention istested on intact, gel-filtered human thrombocytes. The value given isthe K_(i) value for inhibition of the binding of ¹²⁵I-fibrinogenfollowing stimulation with ADP (10 μM) [Literature: Bennett, J. S.;Vilaire, G. J. Clin. Invest. 64, 1393-1401 (1979); Kornecki, E. et al.,J. Biol. Chem. 256, 5696-5701 (1981)].

For this purpose, human thrombocytes were isolated from platelet-richplasma (PRP) by gel filtration on Sepharose 2 B. A suspension ofgel-filtered platelets (GFP) was obtained which contained 4×10⁸platelets/ml. The platelets were incubated at room temperature for 30min in the presence of 40 nmol/l ¹²⁵I-fibrinogen, 10 μM ADP anddifferent concentrations of the test substance. Aliquots of 100 μl werethen added onto 20% sucrose, and the platelets were sedimented by beingcentrifuged for 2 minutes at 12,000 revolutions per minute. Thesupernatant was decanted carefully and completely and the remainingsediment was measured in a gamma counter. The specific binding wasascertained by subtracting the binding in the presence of an excess (10μM) of unlabelled fibrinogen from the total bound radioactivity. Thebinding is given in fmol of ¹²⁵I-fibrinogen/10⁸ platelets. Thedissociation constant K_(i) for the test substance was determined fromthe ¹²⁵I-fibrinogen vs. (non-labelled) test substance displacementexperiments by a computer analysis of the binding data (sigma plot).

In this test, the following results were obtained for the compounds ofthe examples below:

Example: K_(i) (μM), ADP-stimulated  1 0.0132 56 0.0218 57 1.97 580.0092

Test method 3

The inhibition of the binding of fibrinogen to its receptor(glycoprotein IIb/IIIa) which is brought about by the compoundsaccording to the invention is tested on the isolated receptor, which wasisolated from human thrombocytes and immobilized in microtitre plates.The value given is the K_(i) value of the inhibition of the binding of¹²⁵I-fibrinogen [Literature: Fitzgerald, L. A. et al., Anal. Biochem.151, 169-177 (1985) Pytela, R. et al., Science 231, 1559-1562 (1986);Charo, I. F. et al., J. Biol. Chem. 266, 1415-1421 (1991); Scarborough,R. M. et al., J. Biol. Chem. 266, 9359-9362 (1991)]. In this test, thefollowing results were obtained for the compounds of the examples below:

Example: K_(i) (nM), ADP-stimulated  1 0.172 13 0.748 21 1.9 22 0.15 250.175 27 0.107 26 0.117 28 0.078 39 0.948 40 1.99 46 1.23 56 0.486 5737.3 58 0.172

EXAMPLES

The products were identified by way of mass spectra and/or NMR spectra.

Example 1((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

1a, (R,S)-4-(4-Cyanophenyl)-4-methyl-2,5-dioxoimidazolidine

20 g (138 mmol) of p-acetylbenzonitrile, 115.6 g of ammonium carbonate(1.21 mol) and 11.6 g of potassium cyanide (178 mmol) are dissolved in600 ml of a mixture consisting of 50% ethanol and 50% water. The mixtureis stirred at 55° C. for 5 hours and left to stand at room temperatureovernight. The solution is adjusted to pH=6.3 with 6 N HCl andsubsequently stirred at room temperature for 2 hours. The precipitate isfiltered off with suction, washed with water and dried over phosphoruspentoxide under high vacuum.

Yield: 22.23 g (65%)

1b. Methyl((R,S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate

1.068 g of sodium (46.47 mmol) are dissolved, under nitrogen, in 110 mlof abs. methanol. 10 g of(R,S)-4-(4-cyano-phenyl)-4-methyl-2,5-dioxoimidazolidine (46.47 mmol)are added to the clear solution and the mixture is boiled under refluxfor 2 h. 7.75 g (46.48 mmol) of potassium iodide are added and asolution of 4.53 ml of methyl chloroacetate (51.3 mmol) in 5 ml ofmethanol is added dropwise within the space of one hour. The mixture isheated to boiling for 6 hours, left to stand at room temperatureovernight, and then concentrated. The oily residue is chromatographed onsilica gel using methylene chloride/ethyl acetate (9:1).

Yield: 8.81 g (66%)

1c. Methyl((R,S)-4-(4-(ethoxyiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetatehydrochloride

A suspension of 4 g of methyl((R,S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate(13.92 mmol) in 60 ml of abs. ethanol is cooled down to 0° C. Dry HClgas is passed into the suspension, with the temperature being kept under10° C. all the time, until the nitrile band is no longer present in theIR spectrum. 200 ml of diethyl ether are added to the ethanolic solutionand the mixture is left to stand at 4° C. overnight. The precipitate isfiltered off with suction and dried under high vacuum.

Yield: 3.96 g (77%)

1d. Methyl((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetatehydrochloride

3.96 g of methyl((R,S)-4-(4-(ethoxyiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetatehydrochloride (10.7 mmol) are suspended in 40 ml of isopropanol andtreated with 11.9 ml of a 2 N solution of ammonia in isopropanol. Thereaction mixture is stirred at 50° C. for 2 hours. The mixture is cooleddown and 200 ml of diethyl ether are then added to it. The precipitateis filtered off with suction and dried under high vacuum.

Yield: 3.27 g (89%)

1e.((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride

3.27 g of methyl((R,S)-4-(4-aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetatehydrochloride (9.6 mmol) are dissolved in 50 ml of concentratedhydrochloric acid. The solution is heated to boiling for 6 hours andthen concentrated.

Yield: 2.73 g (87%)

1f.((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester hydrochloride

673 mg of DCC (3.06 mmol) are added, at 0° C., to a solution of 1 g of((R,S)-4-(4-(aminoiminomethyl)phenyl-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride (3.06 mmol), 1.27 g of H-Asp(OBu^(t))-Phg-OBu^(t))hydrochloride (3.06 mmol) and 413 mg of HOBt in 10 ml ofdimethylformamide. The mixture is left to stir at 0° C. for one hour andat room temperature for 4 hours. Subsequently, the mixture is left tostand in a cold room over the weekend and the precipitate is thenfiltered off with suction and the filtrate concentrated. Forpurification, the substance is chromatographed on silica gel usingmethylene chloride/methanol/glacial acetic acid/water(8.5:1.5:0.15:0.15).

Yield: 920 mg of oil (still contains acetic acid)

1g.((R,S)-4-(4-Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

920 mg of((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester hydrochloride are dissolved in a mixture consistingof 5.4 ml of trifluoroacetic acid, 0.6 ml of water and 0.6 ml ofdimercaptoethane. The solution is left to stand at room temperature forone hour and is then concentrated under a water suction vacuum. Forpurification, the substance is chromatographed on Sephadex LH20 using amixture of glacial acetic acid, n-butanol and water. The fractionscontaining the pure substance are concentrated. The residue is dissolvedin water and freeze-dried.

Yield: 390 mg

[α]_(D)=+1.3° (c=1, in methanol, 25° C.)

Example 2((R,S)-4-(4-(Aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

2a. Methyl((R,S)-4-(4-cyanophenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetate

3 g of methyl((R,S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate(10.4 mmol) are dissolved, under argon, in 15 ml of anhydrousdimethylformamide. 275.5 mg of a dispersion of sodium hydride in mineraloil (11.4 mmol) are added in an argon countercurrent. The reactionmixture is stirred at room temperature for 15 minutes. Subsequently, 721μm of methyl iodide (11.4 mmol) are added. The mixture is stirred atroom temperature for 4 hours and is then left to stand at roomtemperature overnight. The solution is concentrated. For purification,the substance is chromatographed on silica gel using methylenechloride/ethyl acetate (9.5:0.5). The fractions containing the puresubstance are concentrated.

Yield: 2.14 g of oil (68%)

2b. Methyl((R,S)-4-(4-(ethoxyiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetatehydrochloride

A solution of 2.56 g of methyl((R,S)-4-(4-cyanophenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetate(8.5 mmol) in 40 ml of abs. ethanlo is cooled down to 0° C. Dry HCl gasis passed into the solution, with the temperature being kept below 10°C. all the time, until the nitrile band is no longer present in the IRspectrum. The ethanolic solution is concentrated to 20 ml and thentreated with 200 ml of diethyl ether. The suspension is concentrated anddried under high vacuum.

Yield: 2.27 g (76%)

2c. Methyl((R,S)-4-(4-(aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetatehydrochloride

2.26 g of methyl((R,S)-4-(4-(ethoxyiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetatehydrochloride (6.4 mmol) are suspended in 25 ml of isopropanol andtreated with 7.2 ml of a 2 N solution of ammonia in isopropane. Thereaction mixture is stirred at 50° C. for 2.5 hours. The mixture iscooled down and 200 ml of diethyl ether are then added to it. Theprecipitate is filtered off with suction and dried under high vacuum.

Yield: 1.03 g (45%)

2d.((R,S)-4-(4-(Aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride

1 g of methyl((R,S)-4-(4-(aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetatehydrochloride (3.14 mmol) is dissolved in 20 ml of concentratedhydrochloric acid. The solution is heated to boiling for 6 hours andthen concentrated.

Yield: 770 mg (81%)

2e.((R,S)-4-(4-(Aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester hydrochloride

220 mg of DCC (1 mmol) are added, at 0° C., to a solution of 340 mg of((R,S)-4-(4-(aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride (1 mmol), 415 mg of H-Asp(OBu^(t))-Phg-OBu^(t)hydrochloride (1 mmol) and 135 mg of HOBt in 7 ml of dimethylformamide.0.13 ml of N-ethyl-morphonine is added until a pH of 5.0 is achieved andthe mixture is left stirring at 0° C. for one hour and at roomtemperature for 2 hours. Subsequently, the mixture is left to stand in acold room over the weekend and the precipitate is then filtered off withsuction and the filtrate concentrated. For purification, the substanceis chromatographed on Sephadex LH20 using a mixture consisting ofglacial acetic acid, n-butanol and water. The fractions containing thepure substance are concentrated. The residue is dissolved in water andfreeze-dried.

Yield: 377 mg (57%)

2f.((R,S)-4-(4-(Aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

370 mg of((R,S)-4-(4-(aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenyl-glycinedi-tert-butyl ester hydrochloride (0.53 mmol) are dissolved in a mixtureconsisting of 3.6 ml of trifluoroacetic acid, 0.4 ml of water and 0.4 mlof dimercaptoethane. The solution is left to stand at room temperaturefor one hour and is then concentrated under a water suction vacuum. Forpurification, the substance is chromatographed on Sephadex LH20 using amixture of glacial acetic acid, n-butanol and water. The fractionscontaining the pure substance are concentrated. The residue is dissolvedin water and freeze-dried.

Yield: 210 mg of a white solid (72%)

[α]_(D)=−2.8° (c=1, in methanol, 23° C.)

Example 3((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedimethyl ester hydrochloride

977 mg of DCC (5.66 mmol) are added, at 0° C., to a solution of 1.47 gof((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride (4.4 mmol), 1.45 g of H-Asp(OMe)-Phg-OMehydrochloride (4.4 mmol) and 600 mg of HOBt in 15 ml ofdimethylformamide. The mixture is left stirring at 0° C. for one hourand at room temperature for 8 hours. The precipitate is filtered offwith suction and the filtrate is concentrated. For purification, thesubstance is chromatographed on silica gel using methylenechloride/methanol/glacial acetic acid/water (8:2:0.15:0.15), andsubsequently in methylene chloride/methanol/glacial acetic acid(30:10:0.5). The fractions containing the pure substance areconcentrated. The residue is dissolved in water and freeze-dried.

Yield: 437 mg of a white solid (16%)

Example 4((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinediisopropyl ester hydrochloride

4a. (N-Benzyloxycarbonyl)-L-phenylglycine isopropyl ester

20 g of Z-Phg-OH (70 mmol) are dissolved in a mixture consisting of 26ml of isopropanol and 26 ml of pyridine. A solution of 31.5 ml of 50%propanephosphonic anhydride in ethyl acetate and 350 mg of DMAP areadded and the mixture is stirred at room temperature for 24 hours. Themixture is subsequently concentrated in vacuo and the residue ispartitioned between ethyl acetate and water. The organic phase isextracted by shaking with a solution of potassium hydrogen sulphate (100g of potassium sulphate and 50 g of potassium hydrogen sulphatedissolved in 1 liter of water), with a solution of sodium hydrogencarbonate and with water. The organic phase is dried over sodiumsulphate and concentrated.

Yield 16.74 g of oil (73%).

4b. L-Phenylglycine isopropyl ester hydrochloride

16.74 g of (N-benzyloxycarbonyl)-L-phenylglycine isopropyl ester (51mmol) are dissolved in methanol and hydrogenated catalytically overPd/active charcoal at a pH of 4.6 using an automated burette and whileadding 2 N methanolic HCl. The catalyst is filtered off with suctionthrough kieselguhr and the filtrate is concentrated. The residue istriturated with diethyl ether.

Yield: 9.21 g of a white solid (79%).

4c. C₆₂ -Isopropyl L-aspartate hydrochloride

31 ml (0.16 mol) of thionyl chloride are added slowly to 1000 ml ofisopropanol which have been cooled down to −10° C. 40 g of L-asparticacid (0.3 mol) are then introduced into the solution. The mixture isstirred at 40° C. for 6 hours. Subsequently, the mixture is left tostand at room temperature over the weekend. The solution is concentrateddown to a volume of 250 ml and 500 ml of diethyl ether are then added toit. The precipitate is filtered off with suction. The filtrate isconcentrated further and additional crude product is precipitated out byadding diethyl ether. For purification, 20 g of the crude product arepurified on a column containing 1 kg of acidic aluminium oxide.

Yield: 8.55 g

4d. C_(β)-Isopropyl (N-benzyloxycarbonyl)-L-aspartate cyclohexylaminesalt

8.55 g of C₆₂ -isopropyl L-aspartate hydrochloride (48.8 mmol) aredissolved in a mixture consisting of 110 ml of water and 110 ml ofdioxane, and 4.1 g (48.8 mmol) of sodium hydrogen carbonate are thenadded. 13.4 of N-(benzyloxycarbonyloxy)succinimide (53.8 mmol) areadded, and the mixture is stirred at room temperature for 1 hour. The pHis adjusted to a value of 8 by adding 10 g of sodium hydrogen carbonate.The mixture is stirred at room temperature for 5 hours and thenconcentrated. The residue is partitioned between ethyl acetate and 2 NHCl. The organic phase is extracted by shaking with water, dried oversodium sulphate, and concentrated. The resulting oil (12.35 g) isdissolved in 300 ml of diethyl ether. Cyclohexylamine is added dropwiseto the solution until a pH of 8.0 is reached. The precipitate isfiltered off with suction and washed with diethyl ether.

Yield: 12.84 g (64%).

4e. C_(β)-Isopropyl (N-benzyloxycarbonyl)-L-aspartate

12.84 g of C_(β)-isopropyl (N-benzyloxycarbonyl)-L-aspartatecyclohexylamine salt (31.4 mmol) are suspended in 250 ml of ethylacetate. The suspension is extracted by shaking with 15.7 ml of a 2 Nsulphuric acid (31.4 mmol) and water until a clear solution is produced.The organic phase is washed with potassium hydrogen sulphate solution(100 g of potassium sulphate and 50 g of potassium hydrogen sulphatedissolved in 1 liter of water), dried over sodium sulphate, andconcentrated.

Yield: 8.22 g of oil (85%).

4f. C_(β)-Isopropyl (N-benzyloxycarbonyl)-L-aspartate-L-phenylglycineisopropyl ester

3.36 ml of N-ethylmorpholine and 5.69 g of DCC (25.86 mmol) are added,at 0° C., to a solution of 8 g of Z-L-Asp(OiPr)—OH (25.86 mmol), 5.94 gof H-Phg-OiPr (25.86 mmol) and 3.49 of HOBt in 100 ml ofdimethylformamide. The mixture is left to stir at 0° C. for 1 hour andat room temperature for 4 hours. Subsequently, the mixture is left tostand overnight and the precipitate is then filtered off with suctionand the filtrate concentrated. The residue is dissolved in ethyl acetateand the organic phase is extracted by shaking with a solution ofpotassium hydrogen sulphate (100 g of potassium sulphate and 50 g ofpotassium hydrogen sulphate dissolved in 1 liter of water), with asolution of sodium hydrogen carbonate and with water. It is then driedover anhydrous sodium sulphate and concentrated. The oily residue ischromatographed on silica gel using n-heptane/ethyl acetate (7:3).

Yield: 10.28 g (82%).

4g. C_(β)-Isopropyl L-aspartate-L-phenylglycine isopropyl esterhydrochloride

10.28 g of C_(β)-isopropyl(N-benzyloxycarbonyl)-L-aspartate-L-phenylglycine isopropyl ester (21.2mmol) are dissolved in 250 ml of methanol and catalytically hydrogenatedover Pd/active charcoal at a pH of 4.6 using an automated burette andadding 2 N methanolic HCl. The catalyst is filtered off with suctionthrough kieselguhr and the filtrate is concentrated. The residue wastaken up in water and freeze-dried.

Yield: 6.56 g of a white solid (80%).

4h.((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinediisopropyl ester hydrochloride

1.35 g of DCC (6.12 mmol) are added, at 0° C., to a solution of 2 g of((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride (6.12 mmol), 2.37 g of H-asp(OiPr)-Phg-OiPrhydrochloride (6.12 mmol) and 826.3 mg of HOBt in 15 ml ofdimethylformamide. The mixture is left to stir at 0° C. for 1 hour andat room temperature for 5 hours. Subsequently, the mixture is left tostand in a cold room overnight, and the precipitate is then filtered offwith suction and the filtrate concentrated. For purification, thesubstance is chromatographed on silica gel using methylenechloride/methanol/glacial acetic acid/water (8.5:1.5:0.15:0.15). Thefractions containing the pure substance are concentrated. The residue isdissolved in water and freeze-dried.

Yield: 1.03 g of a white solid (27%).

[α]_(D)=−9.3° (c=1, in methanol, 24° C.).

Example 5

((R,S)-4-(4-(Methoxycarbonylaminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinediisopropyl ester

700 mg of((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinediisopropyl ester hydrochloride (1.1 mmol; see Example 4) are dissolvedin 15 ml of dimethylformamide and treated with 457.4 μl (3.3 mmol) oftriethylamine and 212.6 μl of methyl chloroformate (2.75 mmol). Themixture is left to stir at room temperature for 8 hours and subsequentlyto stand at room temperature overnight. The reaction mixture is filteredand the filtrate is concentrated. The residue is taken up in a solutionof sodium hydrogen carbonate and the aqueous phase is extracted threetimes by shaking with ethyl acetate. The organic phases are combined,dried over sodium sulphate and concentrated. For purification, theamorphous substance is chromatographed on silica gel using methylenechloride/methanol (20:1). The fractions containing the pure substanceare concentrated. The oily residue is triturated with diethyl ether andthe precipitate is filtered off with suction.

Yield: 410 mg of a white solid (55%).

Example 6

3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-benzyloxycarbonylaminopropionicacid

6a. tert-Butyl 3-amino-2-L-benzyloxycarbonylaminopropionate

5 g of 3-amino-2-L-benzyloxycarbonylaminopropionic acid (21 mmol);Bachem Chemie) are suspended in 50 ml of dioxane and treated, whilebeing cooled, with 5 ml of concentrated sulphuric acid. The slightlyyellowish solution is cooled with dry ice and 50 ml of condensedisobutylene are added to it. The mixture is shaken at room temperaturefor 3 days in an autoclave under nitrogen at a pressure of 20atmospheres. Subsequently, excess isobutylene is driven out with astream of nitrogen. The solution is adjusted to a pH of 10 with a 2 Msolution of sodium carbonate (approximately 70 ml) and extracted threetimes by shaking with 200 ml of diethyl ether on each occasion. Theorganic phase is washed with water, dried over sodium sulphate andconcentrated.

Yield: 4.31 g of oil (70%).

6b. tert-Butyl3-(((R,S)-4-(4-(aminoiminomethyl)phenyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-benzyloxycarbonylaminoproprionatehydrochloride

405 mg of DCC (1.84 mmol) are added, at 0° C., to a solution of 600 mgof((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetic and hydrochloride (1.84 mmol; see Example 1), 542 mg oftert-butyl 3-amino-2-L-benzyloxycarbonylaminopropionate (1.84 mmol) and249 mg of HOBt in 5 ml of dimethylformamide. The mixture is left to stirat 0° C. for 1 hour and at room temperature for 6 hours. Subsequently,the mixture is left to stand in a cold room overnight and theprecipitate is then filtered off with suction and the filtrateconcentrated. For purification, the substance is chromatographed onsilica gel using methylene chloride/methanol/glacial acetic acid/water(8.5:1.5:0.15:0.15).

Yield: 680 mg of oil (still contains acetic acid).

6c.3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-benzyloxycarbonylaminopropionicacid

670 mg of tert-butyl3-(((R,S)-4-(4-(aminoiminomethyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-benzyloxycarbonylaminoproprionatehydrochloride are dissolved in a mixture of 3.6 ml of trifluoroaceticacid, 0.4 ml of water and 0.4 ml of dimercaptoethane. After one hour atroom temperature, the mixture is concentrated under a water suctionvacuum. The residue is taken up in water and the aqueous phase isextracted three times with diethyl ether. The organic phase is washedonce with water and the combined aqueous phases are freeze-dried. Forpurification, the substance is chromatographed on Sephadex LH20 using amixture consisting of glacial acetic acid, n-butanol and water. Thefractions containing the pure substance are concentrated. The residue isdissolved in water and freeze-dried.

Yield: 350 mg

[α]_(D)=−12.4° (c=1, in methanol, 25° ).

Example 7

2-Amino-3-(((R,S)-4-(4-(aminoiminomethyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)propionicacid hydrochloride

7a. tert-Butyl2-amino-3-(((R,S)-4-(4-(aminoiminomethyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)propionatedihydrochloride

930 mg of tert-butyl3-(((R,S)-4-(4-(aminoiminomethyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-benzyloxycarbonylaminopropionatehydrochloride (see Example 6b) are dissolved in 25 ml of methanol andhydrogenated catalytically over Pd/active charcoal at a pH of 4.6 usingan automated burette and adding 2 N methanolic HCl. The catalyst isfiltered off with suction through kieselguhr and the filtrate isfreeze-dried. For purification, the substance is chromatographed onsilica gel using methylene chloride/methanol/glacial acetic acid/water(9:4:0.3:0.65).

Yield: 300 mg of a white solid (42%).

2-Amino-3-(((R,S)-4-(4-(aminoiminomethyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)propionicacid hydrochloride

290 mg of tert-butyl2-amino-3-(((R,S)-4-(4-(aminoiminomethyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)propionichydrochloride are dissolved in a mixture of 3.6 ml of trifluoroaceticacid, 0.4 ml of water and 0.3 ml of dimercaptoethane. The solution isstirred at room temperature for one hour and then concentrated under awater suction vacuum. The residue is taken up in water and the aqueousphase is extracted three times with diethyl ether. The organic phase iswashed once with water and the combined aqueous phases are freeze-dried.For purification, the substance is chromatographed on Sephadex LH20using a mixture consisting of glacial acetic acid, n-butanol and water.The fractions containing the pure substance are concentrated. Theresidue is dissolved in water and freeze-dried.

Yield: 39 mg of a white solid (15%).

Example 8

((R,S)-4-(4-(Aminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

8a. Methyl((R,S)-4-(4-(aminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetateacetate

1 g of methyl((R,S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl) (3.48mmol; see Example 1) is dissolved in a mixture consisting of 8 ml ofethanol and 2 ml of 50% acetic acid. 200 mg of 10% Pd/C are added to thesolution which is then hydrogenated at room temperature for 2 hours in ashaking autoclave under a pressure of 3 bar. The catalyst is filteredoff with suction through kieselguhr and the filtrate is concentrated.The oily residue is chromatographed on silica gel using methylenechloride/methanol (8:2).

Yield: 800 mg (79%).

8b.((R,S)-4-(4-(Aminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride

750 mg of methyl((R,S)-4-(4-(aminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetateacetate (2.57 mmol) are dissolved in 15 ml of concentrated HCl. Thesolution is heated to boiling for 6 hours and is then concentrated. Theresidue is taken up in water and freeze-dried.

Yield: 700 mg (87%).

8c.((R,S)-4-(tert-Butoxycarbonylaminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid

300 mg of((R,S)-4-(4-(aminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride (0.96 mmol) are dissolved in a mixture consisting of2 ml of dioxane and 1 ml of water. The solution is adjusted to a pH of8.0 with 1 N NaOH (approximately 1 ml) and subsequently cooled down to0° C. 230 mg of di-tert-butyl dicarbonate (1.05 mmol) are added whilestirring. The reaction mixture is allowed to warm to room temperatureand stirring is continued for a further 3 hours. During this period, thepH is maintained at a value of 8.0 by the continuous addition of 1 NNaOH (approximately 1.2 ml). The reaction mixture is concentrated invacuo. The residue is adjusted, while being cooled (0° C.), to a pH of2.0 with a solution of potassium hydrogen sulphate (100 g of potassiumsulphate and 50 g of potassium hydrogen sulphate dissolved in 1 liter ofwater). The aqueous phase is extracted three times with ethyl acetate.The combined organic phases are extracted by being shaken with water anddried over anhydrous sodium sulphate. The organic phase is concentrated.The residue is taken up in a little water and freeze-dried.

Yield: 340 mg (94%).

8d.((R,S)-4-(4-tert-Butoxycarbonylaminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester

104 μl of N-ethylmorpholine and 176 mg of DCC (0.9 mmol) are added, at0° C., to a solution of 300 mg of((R,S)-4-(tert-butoxycarbonylaminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid (0.8 mmol), 332 mg of H-Asp(OBu^(t))-Phg-OBu^(t) hydrochloride (0.8mmol) and 108 mg of HOBt in 3 ml of dimethylformamide. The mixture isleft to stir at 0° C. for one hour and at room temperature for 4.5hours. Subsequently the mixture is left to stand in a cold roomovernight and the precipitate is then filtered off with suction and thefiltrate is concentrated. For purification, the substance ischromatographed on silica gel using methylene chloride/methanol (20:1).

Yield: 320 mg of oil (54%).

8e.((R,S)-4-(4-(Aminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

270 mg of((R,S)-4-(tert-butoxycarbonylaminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester (0.51 mmol) are dissolved in a mixture consisting of1.8 mol of trifluoroacetic acid, 0.2 ml of water and 0.2 ml ofdimercaptoethane. After one hour at room temperature, the mixture isconcentrated under a water suction vacuum. For purification, thesubstance is chromatographed on Sephadex LH20 using a mixture consistingof glacial acetic acid, n-butanol and water. The fractions containingthe pure substance are concentrated. The residue is dissolved in waterand freeze-dried.

Yield: 160 mg (59%)

[α]_(D)=+1.7° (c=1, in methanol, 23° C.).

Example 9

3-(((R,S)-4-(4-(Aminoiminomethyl)benzyl)-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-benzyloxycarbonylaminopropionicacid

9a. tert-Butyl3-(((R,S)-4-(4-(aminoiminomethyl)benzyl)-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-benzyloxycarbonylaminopropionate

550 mg of DCC (2.7 mmol) are added, at 0° C., to a solution of 726 mg of(R,S)-4-(4-(aminoiminomethyl)benzyl)-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride (2.5 mmol); EP-A-0530505), 736 mg of tert-butyl3-amino-2-L-benzyloxycarbonylaminopropionate (2.5 mmol) and 338 mg ofHOBt in 10 ml of dimethylformamide. Subsequently, the mixture is left tostir at 0° C. for one hour and at room temperature for 3 hours. Themixture is left to stand in a cold room overnight and the precipitate isthen filtered off with suction and the filtrate is concentrated. Theresidue is triturated with a solution of sodium hydrogen carbonate andthen with water. The remaining oil is dissolved in methanol and theinsoluble residue (urea) is filtered off. The solution is concentrated.

Yield: 1.2 g (85%).

9b.3-(((R,S)-4-(4-(Aminoiminomethyl)benzyl)-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-benzyloxycarbonylaminopropionicacid

1.2 g of tert-butyl3-(((R,S)-4-(4-(aminoiminomethyl)benzyl)-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-benzyloxycarbonylaminopropionateare dissolved in a mixture of 10.8 ml of trifluoroacetic acid and 0.8 mlof water. After one hour at room temperature, the solution isconcentrated under a water suction vacuum. The residue is trituratedwith diethyl ether. The precipitate is filtered off with suction. Forpurification, the substance (380 mg) is chromatographed on Sephadex LH20in a mixture consisting of glacial acetic acid, n-butanol and water. Thefractions containing the pure substance are concentrated. The residue isdissolved in water and freeze-dried.

Yield: 56 mg (5%).

Example 10

((R,S)-4-(4-Guanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

10a.((R,S)-4-(4-Benzyloxycarbonylguanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester

300 mg (0.625 mmol) of((R,S)-4-(4-benzyloxycarbonylguanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid (Ex. 11e) are dissolved in 50 ml of dimethylformamide, and 145 mg(0.7 mmol) of DCC and 85 mg (0.625 mmol) of HOBt are added at 0° C. Themixture is subsequently stirred for 1 hour and 260 mg (0.625 mmol) ofH-Asp(OBu^(t))-Phg-OBu^(t) hydrochloride and 86.4 mg (0.75 mmol) ofN-ethylmorpholine are then added. The mixture is stirred at roomtemperature for 4 hours and then concentrated and the residue dissolvedin ethyl acetate; the precipitate is filtered off with suction and theorganic phase is washed with a solution of sodium hydrogen carbonate anda solution of potassium hydrogen sulphate, dried and concentrated. Theresidue is stirred up with ether and filtered off with suction.

Yield: 370 mg (74%).

10b.((R,S)-4-(4-Guanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

370 mg (0.46 mmol) of((R,S)-4-(4-benzyloxycarbonylguanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester are stirred at room temperature for 1 hour togetherwith 3.7 ml of 90% trifluoroacetic acid and the solution is subsequentlyconcentrated under high vacuum. The residue is dissolved in 50 ml ofmethanol and 50 mg of 10% Pd on charcoal are then added and the residueis hydrogenated at room temperature. Once the reaction is complete, thecatalyst is filtered off and the mixture is concentrated and the residueis chromatographed for purification, on Sephadex LH20 using a mixtureconsisting of glacial acetic acid, n-butanol and water. The fractionscontaining the pure substance are concentrated. The residue is dissolvedin water and freeze-dried.

Yield: 123 mg (48%)

Melting point: 180° C.

Example 11

((R,S)-4-(4-Benzyloxycarbonylguanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedimethyl ester

11a. (R,S)-4-(4-Nitrophenyl)-4-methyl-2,5-dioxoimidazolidine

20.8 g (0.32 mol) of potassium cyanide and 96.1 g (1 mol) of ammoniumcarbonate are dissolved in 250 ml of water and carefully added to 49.5 g(0.3 mol) of 4-nitroacetophenone, dissolved in 250 ml of ethanol. Themixture is stirred at 50° C. for 5 hours and then cooled and the productwhich has precipitated out is filtered off with suction and subsequentlywashed with diethyl ether.

Yield: 56.2 g (80%)

Melting point: 237-240° C.

11b. Methyl((R,S)-4-(4-nitrophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate

3.5 g (0.15 mol) of sodium are dissolved, under a nitrogen atmosphere,in 400 ml of methanol. 35.3 g (0.15 mol) of4-((R,S)-4-nitrophenyl)-4-methyl-2,5-dioxoimidazolidine are then addedand the mixture is heated under reflux for 2 hours. Following theaddition of 24.9 g (0.15 mol) of potassium iodide and 16.3 g (0.15 mol)of methyl chloroacetate, the mixture is heated under reflux for afurther 6 hours and then cooled and filtered with suction. The filtrateis concentrated and the residue is stirred up with tert-butyl methylether, filtered off with suction and dried.

Yield: 37.9 g (82%)

Melting point: 177-178° C.

11c. Methyl((R,S)-4-(4-aminophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate

22.2 g (72.2 mmol) of methyl((R,S)-4-(4-nitrophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate in600 ml of ethanol are added carefully to a suspension consisting of 7.4g of calcium chloride, 37 g of zinc dust, 11 ml of water and 7.4 ml ofacetic acid. The mixture is heated under reflux for 4 hours. The hotmixture is filtered and the filtrate is concentrated and ethyl acetateand sodium hydrogen carbonate are added to the remaining residue. Theorganic phase is separated off and concentrated.

Yield: 12.2 g (61%).

11d. Methyl(R,S)-4-(4-benzyloxycarbonylguanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate

3.0 g (10.8 mmol) of methyl((R,S)-4-(4-aminophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate and2.4 g (10.8 mmol) of benzyloxycarbonyl-S-methylisothiourea are stirredat room temperature for 24 hours in 30 ml of methanol and 2.2 ml ofacetic acid. After concentrating, the residue is dissolved in ethylacetate and the organic phase is extracted with acidified water, washeduntil it becomes neutral, and concentrated. The residue ischromatographed on silica gel using ethyl acetate:methanol=9:1.

Yield: 2.85 g (58%)

11e.((R,S)-4-(4-Benzyloxycarbonylguanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid

2.81 g (6.2 mmol) of methyl((R,S)-4-(4-benzyloxycarbonylguanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetateare stirred at 85° C. for 3 hours together with 23 ml of water, 15 ml of6 N hydrochloric acid and 60 ml of acetic acid. After concentrating, theresidue is freeze-dried. For purification, the product ischromatographed on Sephadex LH20 using a homogeneous mixture ofbutanol/glacial acetic acid/water.

Yield: 850 mg (31%).

11f.((R,S)-4-(4-Benzyloxycarbonylguanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedimethyl ester

500 mg (1.13 mmol) of((R,S)-4-(4-benzyloxycarbonylguanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid are dissolved in 30 ml of dimethylformamide. Once the solution hasbeen cooled down to 0° C., 153 mg (1.13 mml) of HOBt and 256 mg (1.24mml) of DCC are added. The mixture is stirred at 0° C. for 1 hour and374 mg (1.13 mmol) of H-Asp(OMe)-Phg-OMe hydrochloride and 0.17 ml (1.36mmol) of N-ethylmorpholine are then added and the mixture issubsequently stirred at room temperature overnight. The dicyclohexylureawhich has precipitated out is filtered off and the filtrate isconcentrated under high vacuum; the residue is dissolved in ethylacetate and the organic phase is washed with a solution of sodiumhydrogen carbonate and a solution of potassium hydrogen sulphate, driedand concentrated. The residue is chromatographed on silica gel using amixture consisting of methylene chloride and methanol=9:1. The fractionscontaining the pure substance are concentrated and freeze-dried.

Yield: 620 mg (77%)

Example 12

Methyl(R,S)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionatehydrochloride

440 mg of DCC (2 mmol) are added, at 0° C., to a solution of 653 mg of((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride (2 mmol), 358 mg of methyl(R,S)-3-amino-3-phenylpropionate (2 mmol) and 270 mg of HOBt in 10 ml ofdimethylformamide. The mixture is left to stir at 0° C. for one hour andat room temperature for 3 hours. Subsequently, the mixture is left tostand overnight and the precipitate is then filtered off with suctionand the filtrate is concentrated. For purification, the substance (1.8g) is chromatographed on Sephadex LH20 using a mixture consisting ofglacial acetic acid, n-butanol and water. The fractions containing thepure substance are concentrated. The residue is dissolved in water andfreeze-dried.

Yield: 597 mg (61%)

Example 13

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionicacid hydrochloride

580 mg of methyl(R,S)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionatehydrochloride (1.19 mmol) are dissolved in 55 ml of concentratedhydrochloric acid and left to stand at room temperature for 5.5 hours.The solution is concentrated. For purification, the substance (540 mg)is chromatographed on Sephadex LH20 using a mixture consisting ofglacial acetic acid, n-butanol and water. The fractions containing thepure substance are concentrated. The residue is dissolved in water andfreeze-dried.

Yield: 477 mg (85%)

[α_(D)]=+2.5° (c=1, in water, 23° C.).

Example 14

((R,S)-4-(4-Guanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedimethyl ester hydrochloride

Example 15

((R,S)-4-(4-Methoxycarbonylguanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylalaninediethyl ester.

Example 16

N_(α)-tert-Butyloxycarbonyl-N_(β)-(((R,S)-4-(4-guanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)hydrazinoaceticacid

Example 17

MethylN_(α)-Benzyloxycarbonyl-N_(β)-(((R,S)-4-(4-benzyloxycarbonylguanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)hydrazinoacetate

Example 18

N_(β)-tert-Butyloxycarbonyl-N_(α)-(((R,S)-4-(4-benzyloxycarbonylguanidinophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)hydrazinoaceticacid

Example 19

(S)-2-tert-Butyloxycarbonylamino-6-((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)hexanoicacid

Example 20

N_(α)-((4-(4-(Aminoiminomethyl)benzylidene)-2,5-dioxoimidazolidin-1-yl)acetyl-N_(β)-(tert-butyloxycarbonyl)hydrazinoaceticacid

The compounds of Examples 21 and 22 are diastereomers.

Example 21

((S orR)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

Diastereomer I

The diastereomeric mixture of((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine(Example 1) is resolved by chromatography on a LiChroprep-RP-18reversed-phase column (10 μm) using a water/acetonitrile mixture (880 mlof water; 120 ml of acetonitrile; 1 ml of trifluoroacetic acid) as theeluent. Fractions which contain the peak which elutes first from thecolumn are concentrated. The residue is taken up on a little water andfreeze-dried.

[α]_(D)=−14° (c=1, in water, 30° C.).

FAB MS: 539 (M+H)⁺

Example 22

((R orS)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

Diastereomer II

In analogy with Example 21, the diastereomer II is isolated from thediastereomeric mixture of((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycineby chromatography on a LiChroprep-RP-18 reversed-phase column (10 μm).For this, the fractions are concentrated which contain the second peakeluting from the column. The residue is taken up on a little water andfreeze-dried.

[α]_(D)=+20° (c=1, in water, 30° C.).

FAB MS: 539 (M+H)⁺

Example 23

((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinemethyl ester

FAB MS: 553 (M+H)⁺

Example 24

((R,S)-4-(4-(Aminoiminomethyl)phenyl)-3-ethyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

FAB MS: 466 (M+H)⁺

Example 25

((R,S)-4-(4-Aminoiminomethyl)phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

FAB MS: 629 (M+H)⁺

Example 26

((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-cyclopropyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

26a. 4-Cyanophenylcyclopropylmethanone

22.5 g of 4-bromophenylcyclopropylmethanone (100 mmol) and 10.3 g ofCuCN (100 mmol) are dissolved in 15 ml of DMF and heated under reflux,with stirring, for 4 hours. The suspension is allowed to cool down to70° C. and is then poured into a solution consisting of 40 g ofiron(III) chloride, 10 ml of conc. HCl and 60 ml of water. The mixtureis stirred at 70° C. for 20 minutes. It is then extracted three timeswith 90 ml of toluene on each occasion. The combined organic phases arewashed with 250 ml of 2N hydrochloric acid and with 250 ml of 2N sodiumhydroxide solution, and then concentrated. The solid residue istriturated with petroleum ether and filtered off with suction.

Yield: 14.57 g (85%)

FAB MS: 172 (M+H)⁺

26b,((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-cyclopropyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

The synthesis is carried out in analogy with Example 1 proceeding from4-cyanophenylcyclopropylmethanone.

FAB MS: 565 (M+H)⁺

Example 27

((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-ethyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

The synthesis is carried out in analogy with Example 26 proceeding from1-(4-bromophenyl)-1-propanone.

FAB MS: 553 (M+H)⁺

Example 28

((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-benyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

The synthesis is carried out in analogy with Example 26 proceeding from2-phenyl-1-(4-bromophenyl)-1-ethanone.

FAB MS: 615 (M+H)⁺

Example 29

((R,S)-4-(4-Aminoiminomethyl)phenyl)-4-tert-butyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

29a. 4-Bromophenyl-tert-butylmethanone

21 g of freshly powdered, anhydrous potassium hydroxide (375 mmol) areoverlaid with 50 ml of anhydrous toluene. 20 mg of 18-crown-6 (0.75mmol) and 9.95 g of 4-bromoacetophenone (50 mmol) are added. The mixtureis heated to 70° C. 24.94 ml of iodomethane (395 mmol) are added slowlyto the reaction solution which is then stirred at 70° C. for 3.5 hours.The organic phase is extracted with water. The aqueous phase isextracted twice with diethyl ether. The organic phases are combined,dried over sodium sulphate and concentrated. The crude product (11.46 g)is alkylated once more by the above procedure since the reaction hasstill not gone to completion. The resulting product (10.86 g) ispurified by means of high vacuum distillation using a silvered jacketedcolumn.

Yield: 3.9 g (32%)

FAB MS: 242 (M+H)⁺

29b.((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-tert-butyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

The synthesis is carried out in analogy with Example 26 proceeding from4-bromophenyl-tert-butylmethanone.

FAB MS: 581 (M+H)⁺

Example 30

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-pentylcarbonylaminopropionicacid

FAB MS: 475 (M+H)⁺

Example 31

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-pentylcarbonylaminopropionicacid

FAB MS: 489 (M+H)⁺

Example 32

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-butylsulphonylaminopropionicacid

FAB MS: 497 (M+H)⁺

Example 33

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-butylsulphonylaminopropionicacid

FAB MS: 511 (M+H)⁺

Example 34

2-((R,S)-4-(4-Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-N-((R,S)-1-benzyloxycarbonyl-2-(3-phenylureidosulphonyl)ethyl)acetamide

FAB MS: 650 (M+H)⁺

Example 35

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(3-hydroxy-4-methoxyphenyl)propionicacid

FAB MS: 484 (M+H)⁺

Example 36

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(4-hydroxy-3-methoxyphenyl)propionicacid

FAB MS: 484 (M+H)⁺

Example 37

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(4-ethoxyphenyl)propionicacid

FAB MS: 482 (M+H)⁺

Example 38

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(1-naphthyl)propionicacid

FAB MS: 488 (M+H)⁺

Example 39

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(3-nitrophenyl)propionicacid

FAB MS: 483 (M+H)⁺

Example 40

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(4-hydroxycarbonylphenyl)propionicacid

FAB MS: 482 (M+H)⁺

Example 41

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(3-benzyloxyphenyl)propionicacid

FAB MS: 544 (M+H)⁺

Example 42

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(3-hydroxycarbonylphenyl)propionicacid

FAB MS: 482 (M+H)⁺

Example 43

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(3-phenoxyphenyl)propionicacid

FAB MS: 530 (M+H)⁺

Example 44

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(3,4,5-trimethoxyphenyl)propionicacid

FAB MS: 528 (M+H)⁺

Example 45

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(4-hydroxyphenyl)priopionicacid

FAB MS: 454 (M+H)⁺

Example 46

(R,S)-3-(((R,S)-4-(4-Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(4-phenylphenyl)propionicacid

FAB MS: 514 (M+H)

Example 47

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(3-pyridyl)propionicacid

FAB MS: 439 (M+H)⁺

Example 48

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)butyricacid

FAB MS: 376 (M+H)⁺

Example 49

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-cyclohexylpropionicacid

FAB MS: 444 (M+H)⁺

Example 50

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionicacid

FAB MS: 452 (M+H)⁺

Example 51

Ethyl(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionatehydrochloride

FAB MS: 480 (M+H)⁺

Example 52

(R,S)-3-(((R,S)-4-(4-(Aminoiminomethyl)phenyl)-3-ethyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionicacid

FAB MS: 466 (M+H)⁺

Example 53

Ethyl(R,S)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl)-3-ethyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionatehydrochloride

FAB MS: 494 (M+H)⁺

Example 54

Ethyl(R,S)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionatehydrochloride

FAB MS: 466 (M+H)⁺

Example 55

Ethyl (S)-3-(((R orS)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionatehydrochloride

The compound is derived from the diastereomer II of Example 58.

340 mg of (S)-3-(((R orS)-4-(4-aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionicacid (0.78 mmol) (Example 58) are dissolved in 60 ml of a 2N ethanolicsolution of HCl and left to stand at room temperature for 2 hours. Thesolution is concentrated and the residue is dissolved in water. Thissolution is filtered and freeze-dried.

Yield: 375 mg of a white solid (96%).

[α]_(D)=−55.5° (c=1, in water, 21° C.).

FAB MS: 466 (M+H)⁺

Example 56

(S)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionicacid hydrochloride

12.37 g of ethyl(S)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino-3-phenylpropionatehydrochloride (26.6 mmol) (Example 71) are dissolved in 200 ml ofconcentrated hydrochloric acid and left to stand at room temperature for7.5 hours. The solution is concentrated. 200 ml of concentratedhydrochloric acid are added to the residue and this solution is left tostand at room temperature for 7.5 hours and then concentrated. 11.6 g ofcrude product are obtained.

For purification, a part of the substance (255 mg) is chromatographed onSephadex LH20 in a mixture consisting of glacial acetic acid, n-butanoland water. The fractions containing the pure substance are concentrated.The residue is dissolved in water and freeze-dried.

Yield: 232 mg.

FAB MS: 438 (M+H)⁺

Example 57

Diastereomer I:

(S)-3-(((S orR)-4-(4-Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionicacid

The diastereomeric mixture of(S)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionicacid hydrochloride (Example 56) is resolved by chromatography on aLiChroprep RP-18 reversed-phase column (10 μm) using awater/acetronitrile mixture (920 ml of water; 80 ml of acetonitrile; 1 gof ammonium acetate) as the eluent. For this purpose, 500 mg of thediastereomeric mixture are in each case loaded onto a column having acharging volume of 450 ml. Fractions containing the peak eluting firstfrom the column are concentrated. The ammonium acetate is removed byfreeze-drying three times.

Yield per column run: 245 mg (49%)

[α]_(D)=−110.4° (c=1, in water, 30° C.)

FAB MS: 438 (M+H)⁺

Example 58

Diastereomer II:

(S)-3-(((R orS)-4-(4-Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionicacid

In analogy with Example 57, the diastereomer II is isolated from thediastereomeric mixture of(S)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionicacid hydrochloride (Example 56) by chromatography on a LiChroprep-RP-18reversed-phase column (10 μm). For this purpose, the fractions areconcentrated which contain the second peak eluting from the column. Theammonium acetate is removed by freeze-drying three times.

Yield per column run: 200 mg (40%)

[α]_(D)=−62.8° (c=1, in water, 30° C.)

FAB MS: 438 (M+H)⁺

Example 59

Diastereomer III

(R)-3-(((S orR)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionicacid

145 mg of the diastereomeric mixture of(R)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolin-1-yl)acetylamino)-3-phenylpropionicacid hydrochloride (Example 61) are resolved by chromatography on aLiChroprep-RP-18 reversed-phase column (10 μm) in analogy with Example57. Fractions which contain the first peak eluting from the column areconcentrated. The ammonium acetate is removed by freeze-drying threetimes.

Yield: 60 mg (41%).

[α]_(D)=+92.7° (c=1, in water, 30° C.)

FAB MS: 438 (M+H)⁺

Example 60

Diastereomer IV

(R)-3-(((R orS)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionicacid

In analogy with Example 59, the diastereomer IV is isolated from thediastereomeric mixture of(R)-3-(((R,S)-4-(4-aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-phenylpropionic acid hydrochloride (Example 61) bychromatography on a LiChroprep-RP-18 reversed-phase column (10 μm). Forthis purpose, the fractions are concentrated which contain the secondpeak eluting from the column. The ammonium acetate is removed byfreeze-drying three times.

Yield: 63 mg (43%)

[α]_(D)=+51.4° (c=1, in water, 30° C.)

FAB MS: 438 (M+H)⁺

Example 61

(R)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionicacid hydrochloride

The substance is prepared in analogy with Examples 71 and 56. In thiscase, the synthesis proceeds from (S)-phenylglycine.

FAB MS: 438 (M+H)⁺

Example 62

The compound is derived from the diastereomer I of Example 57.

Ethyl (S)-3-(((S orR)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionatehydrochloride

FAB MS: 466 (M+H)⁺

Example 63

The compound is derived from the diastereomer II of Example 58.

Methyl (S)-3-(((R orS)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionatehydrochloride

FAB MS: 452 (M+H)⁺

Example 64

The compound is derived from the diastereomer II of Example 58.

Isopropyl (S)-3-(((R orS)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionatehydrochloride

FAB MS: 480 (M+H)⁺

Example 65

(R,S)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-N-methylamino))-3-(3-pyridyl)-propionicacid

FAB MS: 453 (M+H)⁺

Example 66

(R,S)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-N-methylamino))-3-phenylpropionicacid

FAB MS: 452 (M+H)⁺

Example 67

(R,S)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-(3,4-methylenedioxyphenyl)propionicacid

FAB MS: 482 (M+H)⁺

Example 68

(2-((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)-L-aspartyl-1-adamantylamide

68a. (N-Benzyloxycarbonyl)-L-aspartic acid-C_(β)-tert-butylester-1-adamantylamide

1.69 ml of N-ethylmorpholine (13 mol) and 2.86 g of DCC (13 mmol) areadded, at 0° C., to a suspension of 4.2 g of Z-L-Asp(OBu^(t))—OH (13mmol), 1.97 g of 1 aminoadamantane (13 mmol) and 1.76 g of HOBt (13mmol) in 140 ml of dimethylformamide. The mixture is left to stir at 0°C. for 1 hour and at room temperature for 3 hours. Subsequently, themixture is left to stand overnight and the precipitate is then filteredoff with suction and the filtrate is concentrated. The residue is takenup in a solution of sodium hydrogen carbonate and the aqueous phase isextracted by shaking with ethyl acetate. The organic phase is extractedby shaking with a solution of potassium hydrogen sulphate (100 g ofpotassium sulphate and 50 g of potassium hydrogen sulphate dissolved in1 liter of water), with a solution of sodium hydrogen carbonate and withwater. It is dried over anhydrous sodium sulphate and concentrated.

Yield: 6.21 g (crude product).

68b. L-Aspartic acid-C_(β)-tert-butyl ester-1-adamantylamidehydrochloride

6.21 g of (N-benzyloxycarbonyl)-L-aspartic acid-C_(β)-tert-butylester-1-adamantylamide (crude product) are dissolved in 50 ml ofmethanol and catalytically hydrogenated over Pd/active charcoal at a pHof 4.6 using an automated burette and adding 2N methanolic HCl. Thecatalyst is filtered off with suction through kieselguhr and thefiltrate is concentrated. The residue is triturated with diethyl ether,filtered off with suction and dried.

Yield: 4 g (85% based on quantity of Z-L-Asp(OBu^(t))—OH employed);

FAB MS (M+H)⁺=323.

68c.(2-((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)-L-aspartyl-C_(β)-tert-butylester-1-adamantylamide hydrochloride

0.26 ml of N-ethylmorpholine (2 mmol) and 440 mg of DCC (2 mmol) areadded, at 0° C., to a suspension of 654 mg of2-((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride (2 mmol; see Example 1), 718 mg of L-asparticacid-C_(β)-tert-butyl ester-1-adamantylamide hydrochloride (2 mmol) and270 mg of HOBt (2 mmol) in 20 ml of dimethylformamide. The mixture isleft to stir at 0° C. for 1 hour and at room temperature for 3 hours.Subsequently, the mixture is left to stand at room temperature overnightand the precipitate is then filtered off with suction and the filtrateis concentrated. The residue is taken up in a solution of sodiumhydrogen carbonate and the aqueous phase is extracted by shaking withpentanol. The organic phase is extracted by shaking with a solution ofpotassium hydrogen sulphate and with water. It is dried over anhydroussodium sulphate and concentrated. The residue is triturated with diethylether, filtered off with suction and dried.

Yield: 1.35 g (crude product).

68d.(2-((R,S)-4-(4-Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)-L-aspartyl-1-adamantylamide

1.35 g of(2-((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)-L-aspartyl-C_(β)-tert-butylester-1-adamantylamide hydrochloride are dissolved in a mixture of 12.15ml of trifluoroacetic acid, 1.35 ml of water and 1.35 ml ofdimercaptoethane. After 1 hour at room temperature, the mixture isconcentrated under a water suction vacuum. The residue is trituratedwith diethyl ether, filtered off with suction and dried. Forpurification, the substance is chromatographed on Sephadex LH20 in amixture consisting of glacial acetic acid, n-butanol and water. Thefractions containing the pure substance are concentrated. The residue isdissolved in water in the presence of a little acetic acid andfreeze-dried.

Yield: 1.02 g; FAB MS (M+H)⁺=539

Example 69

(2-((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)-L-aspartyl-2-adamantylamide

69a. (N-benzyloxycarbonyl)-L-aspartic acid-C_(β)-tert-butylester-2-adamantylamide

1.69 ml of N-ethylmorpholine (13 mmol) and 2.86 g of DCC (13 mmol) areadded, at 0° C., to a suspension of 4.2 g of Z-L-Asp(OBu^(t))—OH (13mmol) and 1.76 g of HOBt (13 mmol) in 40 ml of dimethylformamide. Themixture is left to stir at 0° C. for 1 hour and at room temperature for3 hours. Subsequently, the mixture is left to stand overnight and theprecipitate is then filtered off with suction and the filtrate isconcentrated. The residue is taken up in a solution of sodium hydrogencarbonate and the aqueous phase is extracted by shaking with ethylacetate. The organic phase is extracted by shaking with a solution ofpotassium hydrogen sulphate, with a solution of sodium hydrogencarbonate, and with water. It is dried over anhydrous sodium sulphateand concentrated.

Yield: 6.32 g (crude product).

69b. L-Aspartic acid-C_(β)-tert-butyl ester-2-adamantylamidehydrochloride

6.32 g of (N-benzyloxycarbonyl)-L-aspartic acid-C_(β)-tert-butylester-2-adamantylamide (crude product) are dissolved in 50 ml ofmethanol and catalytically hydrogenated over Pd/active charcoal at a pHof 4.6 using an automated burette and adding 2N methanolic HCl. Thecatalyst is filtered off with suction through kieselguhr and thefiltrate is concentrated. The residue is dissolved in diethyl ether andconcentrated. An amorphous solid is obtained.

Yield: 4 g (85% based on quantity of Z-L-Asp(OBu^(t))—OH employed;

FAB MS (M+H)⁺=323

69c.(2-((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)-L-aspartyl-C_(β)-tert-butylester-2-adamantylamide hydrochloride

0.26 ml of N-ethylmorpholine (2 mmol) and 440 mg of DCC (2 mmol) areadded, at 0° C., to a suspension of 654 mg of2-((R,S)-4-(aminoiminomethyl)phenyl-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride (2 mmol; see Example 1), 718 mg of L-asparticacid-C_(β)-tert-butyl ester-2-adamantylamide hydrochloride (2 mmol) and270 mg of HOBt (2 mmol) in 20 ml of dimethyl formamide. The mixture isleft to stir at 0° C. for 1 hour and at room temperature for 2 hours.Subsequently, the mixture is left to stand at room temperature overnightand the precipitate is then filtered off with suction and the filtrateis concentrated. The residue is taken up in a solution of sodiumhydrogen carbonate and the aqueous phase is extracted by shaking withpentanol. The organic phase is extracted by shaking with a solution ofpotassium hydrogen sulphate and with water. It is dried over anhydroussodium sulphate and concentrated. The residue is triturated with diethylether, filtered off with suction and dried.

Yield: 1.27 g (crude product).

69d.(2-((R,S)-4-(4-(Aminoiminomethyl)phenyl-4-methyl-2,5-dioxoimidazolidin-1yl)acetyl)-L-aspartyl-2-adamantylamide

1.27 g(2-((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)-L-aspartyl-C_(β)-tert-butylester-2-adamantylamide hydrochloride are dissolved in a mixture of 11.43ml of trifluoroacetic acid, 1.27 ml of water and 1.27 ml ofdimercaptoethane. After 1 hour at room temperature, the mixture isconcentrated under a water suction vacuum. The residue is trituratedwith diethyl ether, filtered off with suction and dried. Forpurification, the substance is chromatographed on Sephadex LH20 in amixture consisting of glacial acetic acid, n-butanol and water. Thefractions containing the pure substance are concentrated. The residue isdissolved in water in the presence of a little acetic acid andfreeze-dried.

Yield: 615.8 mg; FAB MS (M+H)⁺=539

Example 70

(2-((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)-L-aspartyl-(1-adamantylmethyl)amide

70a. (N-Benzyloxycarbonyl)-L-aspartic acid-C_(β)-tert-butylester-(1-adamantylmethyl)amide

2.66 g of DCC (12.1 mmol) are added, at 0° C., to a suspension of 3.91 gof Z-L-Asp(OBu^(t))—OH (12.1 mmol) in 60 ml of dimethylformamide. Themixture is left to stir at 0° C. for 1 hour and at room temperature for2 hours. Subsequently, the mixture is left to stand overnight and theprecipitate is then filtered off with suction and the filtrate isconcentrated. The residue is taken up in a solution of sodium hydrogencarbonate and the aqueous phase is extracted by shaking with ethylacetate. The organic phase is extracted by shaking with a solution ofpotassium hydrogen sulphate, with a solution of sodium bicarbonate andwith water. It is dried over anhydrous sodium sulphate and concentrated.

Yield: 6 g (crude product).

70b. L-Aspartic acid-C_(β)-tert-butyl ester-(1-adamantylmethyl)amidehydrochloride

6 g of (N-benzyloxycarbonyl)-L-aspartic acid-C_(β)-tert-butylester-(1-adamantylmethyl)amide (crude product) are dissolved in 50 ml ofmethanol and hydrogenated catalytically over Pd/active charcoal at a pHof 4.6 using an automated burette and while adding 2N methanolic HCl.The catalyst is filtered off with suction through kieselguhr and thefiltrate is concentrated. The residue is triturated with diethyl ether,filtered off with suction and dried.

Yield: 3.85 g (85% based on the quantity of Z-L-Asp(OBu^(t))—OHemployed); FAB MS (M+H)⁺=337.

70c.(2-((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-C_(β)-tert-butylester-(1-adamantylmethyl)amide hydrochloride

0.26 ml of N-ethylmorpholine (2 mmol) and 440 mg of DCC (2 mmol) areadded, at 0° C., to a suspension of 654 mg of2-((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetichydrochloride (2 mmol; see Example 1), 746 mg of L-asparticacid-C_(β)-tert-butyl ester-(1-adamantylmethyl)amide hydrochloride (10mmol) and 270 mg of HOBt (10 mmol) in 20 ml of dimethylformamide. Themixture is left to stir at 0° C. for 1 hour and at room temperature for3 hours. Subsequently, the mixture is left to stand at room temperatureovernight and the precipitate is then filtered off with suction and thefiltrate is concentrated. The residue is taken up in a solution ofsodium hydrogen carbonate and the aqueous phase is extracted by shakingwith pentanol. The organic phase is extracted by shaking with a solutionof potassium hydrogen sulphate and with water. It is dried overanhydrous sodium sulphate and concentrated. The residue is trituratedwith diethyl ether, filtered off with suction and dried.

Yield: 1.28 g (crude product).

70d.(2-((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1yl)acetyl-L-aspartyl-(1-adamantylmethyl)amide

1.28 g of(2-((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1yl)acetyl)-L-aspartyl-C_(β)-tert-butylester-(1-adamantylmethyl)amide hydrochloride are dissolved in a mixtureof 11.52 ml of dimercaptoethane. After 1 hour at room temperature, themixture is concentrated under a water suction vacuum. The residue istriturated with diethyl ether, filtered off with suction and dried. Forpurification, the substance is chromatographed on Sephadex LH20 in amixture consisting of glacial acetic acid, n-butanol and water. Thefractions containing the pure substance are concentrated. The residue isdissolved in water in the presence of a little acetic acid andfreeze-dried.

Yield: 841.1 mg; FAB MS (M+H)⁺=553.

Example 71

Ethyl(S)-3-(((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionatehydrochloride

71a. (R)-2-Amino-2-phenylethanol

20 g (920 mmol) of lithium borohydride are dissolved in 420 ml ofabsolute tetrahydrofuran. 233.5 ml (1.84 mol) of trimethylchlorosilaneare added dropwise, while stirring, and 69.5 g (0.46 mol) of(RS)-phenylglycine are then added in portions within the space of 4hours. The reaction mixture is stirred at room temperature overnight.690 ml of methanol are ten added and the mixture is stirred at roomtemperature for 2 hours and concentrated in vacuo. The residue isdissolved, while stirring, in 690 ml of a 20% aqueous solution ofpotassium hydroxide. The aqueous phase is extracted three times withethyl acetate. The combined organic phases are washed with water, driedover magnesium sulphate and concentrated in vacuo.

Yield: 41.2 g (65.3%); FAB MS (M+H)⁺=138.

71b. (R)-2-Benzyloxycarbonylamino-2-phenylethanol

4.5 g (295 mmol) of (R)-2-amino-2-phenylethanol are dissolved in 385 mlof absolute dimethylformamide. 73.5 g ofN-(benzyloxycarbonyloxy)succinimide (295 mmol) are added, at 0° C. andwhile stirring, and the mixture is then stirred at 0° C. for 1 hour. Theice bath is removed and the mixture is left to stand at room temperaturefor 48 h. The reaction solution is concentrated in vacuo and the residueis then taken up in 500 ml of ethyl acetate. The organic phase is washedtwice with a 10% aqueous solution of citric acid and once with water. Itis then dried over anhydrous sodium sulphate and concentrated. Theresulting crystalline crude product (82.3 g) is once again dissolved inethyl acetate. The organic phase is washed twice with a 10% aqueoussolution of citric acid and once with water. Recrystallizationsubsequently takes place from ethyl acetate/petroleum ether.

Yield: 74.6 g (93.3%); FAB MS (M+H)⁺=272.

71c.((R)-2-Benzyloxycarbonylamino-2-phenylethyl)-4-methylphenylsulphonate

53.9 g of (R)-2-benzyloxycarbonylamino-2-phenylethanol (198.7 mmol) aredissolved in a mixture consisting of 500 ml of methylene chloride and80.3 ml (993.5 mmol) of pyridine. 45.5 g (238.4 mmol) of tosyl chloridein 240 ml of methylene chloride are added, at 0° C. and while stirring,and the mixture is left to stir at room temperature for 7 hours. Afurther 11.36 g of tosyl chloride (59.61 mmol) are added. The mixture isleft to stir at 0° C. for 5 hours. The mixture is then left to stand atroom temperature overnight and concentrated in vacuo. The residue istaken up in ethyl acetate. The organic phase is washed three times witha 10% aqueous solution of citric acid and twice with water, dried overmagnesium sulphate and concentrated in vacuo. The residue is trituratedwith diethyl ether, filtered off with suction, washed with diethyl etherand dried over phosphorus pentoxide. Yield: 60.9 g (72%). The motherliquor is concentrated, taken up in n-heptane/ethyl acetate (6:4) andchromatographed on silica gel. Yield: 3.5 g (4.2%).

Total yield: 64.4 g (76.2%); FAB MS (M+H)⁺=426.

71d. (S)-3-Benzyloxycarbonylamino-3-phenylpropionitrile

60.5 g of((R)-2-benzyloxycarbonylamino-2-phenylethyl)-4-methylphenylsulphonate(142.2 mmol) are dissolved in 675 ml of dimethylformamide. 13.9 g ofpotassium cyanide (213.3 mmol), 5.64 g of 18-crown-6 (21.33 mmol) and520 mg of potassium iodide (3.13 mmol) are added and the mixture isstirred at 50° C. for 20 hours. The reaction solution is poured into 500ml of ice water and this mixture is subsequently stirred at 0° C. for 5hours. The mixture is filtered with suction and the precipitate isdissolved in ethyl acetate. The organic phase is washed three times withwater, dried over magnesium sulphate and concentrated in vacuo. Theresidue is triturated with diethyl ether, filtered off with suction,washed with diethyl ether and dried over phosphorus pentoxide.

Yield: 25.3 g (63.5%); FAB MS (M+H)⁺=281.

71e. Ethyl (S)-3-benzyloxycarbonylamino-3-phenylpropionate

15 g of (S)-3-benzyloxycarbonylamino-3-phenylpropionitrile (53.51 mmol)are suspended in a mixture consisting of 110 ml of absolute ethanol and30 ml of dioxane. HCl gas is passed in, while stirring and cooling, at10-15° C. After a short time a clear solution is formed. Further HCl gasis passed in, while cooling, until starting material can no longer bedetected in a thin layer chromatogram. Nitrogen is then passed throughthe reaction solution for 15 minutes and the mixture is subsequentlyconcentrated in vacuo. Water is added to the residue until a lastingturbidity is obtained. The mixture is stirred at room temperature for 30minutes and the aqueous phase is then extracted three times with ethylacetate. The combined organic phases are washed with water, dried overmagnesium sulphate and concentrated in vacuo. The residue is taken up inethyl acetate/petroleum ether (1:1) and chromatographed on silica gel.

Yield: 10.55 g (60%); FAB MS (M+H)⁺=328.

71f. Ethyl (S)-3-amino-3-phenylpropionate hydrochloride

10.29 g of ethyl (S)-3-benzyloxycarbonylamino-3-phenylpropionate (31.44mmol) are dissolved in 125 ml of ethanol and hydrogenated catalyticallyover Pd/active charcoal at a Ph of 4 using an automated burette andwhile adding 2N ethanolic HCl. The catalyst is filtered off with suctionthrough kieselguhr and the filtrate is concentrated. The residue istriturated with diethyl ether, filtered off with suction, washed withdiethyl ether and dried over phosphorus pentoxide.

Yield: 5.05 g (70%); FAB MS (M+H)⁺=194.

71g. Ethyl(S)-3-(((R,S)-4-(4-aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionatehydrochloride

10.4 ml of N-ethylmorpholine (80 mmol) and 17.6 g of DCC (80 mmol) areadded, at 0° C., to a solution of 26.14 g of((R,S)-4-(4-(aminoiminomethyl)phenyl-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid hydrochloride (80 mmol) (Example 1), 18.37 g of ethyl(S)-3-amino-3-phenylpropionate hydrochloride (80 mmol) and 10.8 g ofHOBt in 400 ml of dimethylformamide. The mixture is left to stir at 0°C. for 1 hour and at room temperature for 3 hours. The mixture issubsequently left to stand overnight and the precipitate is thenfiltered off with suction and the filtrate is concentrated. Forpurification, the oily residue (89 g) is chromatographed on SephadexLH20 in a mixture consisting of glacial acetic acid, N-butanol andwater. The fractions containing the pure substance are concentrated. Theresidue is dissolved in water and freeze-dried.

Yield: 35 g (94%); FAB MS (M+H)⁺=466.

What is claimed is:
 1. 5-Membered ring heterocycle of the formula I,

in which W represents R¹-A—C (R¹³) or R¹-A—C═C; Y represents a carbonylgroup, a thiocarbonyl group or a methylene group; Z represents N (R⁰),oxygen, sulphur or a methylene group; A denotes a (C₁-C₆)-alkylene,(C₃-C₇)-cycloalkylene, phenylene, phenylene-(C₁-C₆)-alkyl,(C₁-C₆)-alkylene-phenyl or phenylene-(C₂-C₆)-alkenyl divalent radical,or a divalent radical of a 5-membered or 6-membered saturated orunsaturated ring containing 0, 1 or 2 nitrogen atoms and substituted by0, 1, or 2 (C₁-C₆)-alkyl or doubly bonded oxygen or sulphur; B denotes a(C₁-C₆)-alkylene, (C₂-C₆)-alkenylene, phenylene, phenylene-(C₁-C₃)-alkylor (C₁-C₃)-alkylene-phenyl divalent radical; D represents C(R²) (R³),N(R³) or CH═C(R³); E denotes tetrazolyl, (R⁸O)₂P(O), HOS (O)₂, R9NHS(O)₂or R¹⁰CO; R and R⁰ denote, independently of each other, hydrogen,(C₁-C₈) alkyl, (C₃-C₈) alkyl, (C₃-C₈)-cycloalkyl, substituted orunsubstituted (C₆-C₁₄)-aryl, or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which issubstituted or unsubstituted in the aryl radical; R¹ represents X—NH—C(═NH)—(CH₂)_(p) or X¹-NH-(CH²)_(p), where p is an integer from 0 to 3; Xdenotes hydrogen, (C₁-C₆) alkyl, (C₁-C₆) alkylcarbonyl, (C₁-C₆)-alkoxycarbonyl, C₁-C₁₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl,substituted or unsubstituted (C₆-C₁₄)-arylcarbonyl, substituted orunsubstituted (C₆-C₁₄)-aryloxycarbonyl,(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl which is unsubstituted orsubstituted in the aryl radical (R⁸O)₂P(O), cyano, hydroxyl,(C₁-C₆)-alkoxy, (C₅-C₁₄)-aryl-(C₁-C₆)-alkoxy which is substituted orunsubstituted in the aryl radical, or amino; X¹ has one of the meaningsof X or denotes R′-NH—C (═N—R″), where R′ and R″, independently of eachother, have the meanings of X; R² denotes hydrogen, (C₁-C₈)-alkyl,substituted or unsubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkylwhich is substituted or unsubstituted in the aryl radical, (C₃-C₈)-alkylwhich is substituted or unsubstituted in the aryl radical, or(C₃-C₈)-cycloalkyl; R³ denotes COOR¹⁵, CON (CH₃)R¹⁵ or CONHUR¹⁵; R⁸denotes hydrogen, (C₁-C₁₈)-alkyl, substituted or unsubstituted(C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁C₈)-alkyl which is unsubstituted orsubstituted in the aryl radical; R⁹ denotes hydrogen, aminocarbonyl,(C₁-C₁₈)-alkylaminocarbonyl, (C₃-C₈)-cycloalkylaminocarbonyl,substituted or unsubstituted (C₆-C₁₄)-arylaminocarbonyl, (C₁-C₁₈)-alkyl,substituted or unsubstituted (C₆-C₁₄)-aryl, or (C₃-C₈)-cycloalkyl; R¹⁰denotes hydroxyl, (C₁-C₁₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy which isunsubstituted or substituted in the aryl radical, substituted orunsubstituted (C₆-C₁₄)-aryloxy, amino or mono- ordi-((C₁-C₁₈)-alkyl)-amino; R¹³ denotes hydrogen, (C₁-C₆)-alkyl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which is substituted or unsubstituted in thearyl radical, or (C₃-C₈)-cycloalkyl; R¹⁵ represents R¹⁶-(C₁-C₆)-alkyl orrepresents R¹⁶; R¹⁶ represents 6- to 24-membered bicyclic or tricyclicradical which is saturated or partially unsaturated and which containsform zero to four identical or different heteroatoms from the groupnitrogen, oxygen and sulphur, and which is unsubstituted or substitutedby one or more identical or different sustituents from the group(C₁-C₄)-alkyl and oxo; b, c, d, and f, independently of each other,represent 0 or 1, but cannot all simultaneously be 0; e, g, and h,independently of each other, represent integers from 0 to 6; where,however, when at the same time, W represents R¹-A—CH or R¹-A—CH═C, Drepresents N (R³) and c, d, and f represent 0, R³ cannot when representsCOOR^(a) where R^(a) represents methyl which is substituted by a9-fluorenyl radical, or the physiologically tolerated salts thereof. 2.5-Membered ring heterocycle of the formula I according to claim 1 inwhich W represents R′-A—CH═C in which A represents a phenylene radical,or W represents R¹-A—C(R¹³) in which A represents a methylene, ethylene,trimethylene, tetramethylene, cyclohexylene, phenylene orphenylene-methyl divalent radical; B represents a methylene, ethylene,trimethylene, tetramethylene, vinylene or phenylene divalent radical; Edenotes R⁹NHS (O) ₂ or R¹⁰CO; R and R⁰ denote, independently of eachother, hydrogen, (C₁-C₆)-alkyl or benzyl; R¹ represents X—NH—C(αNH),X—NH—C (═NX)-NH or X—NH—CH₂; X represents hydrogen,(C₁-C₆)-alkylcarbonyl, (C₁-C₆)-alkoxy-caronyl,(C₁-C₆)-alkylcarbonyloxy-(C₁-C₆-alkoxycarbonyl or(C₆-C₁₄)-aryl-(C₁-C₆)-alkoxycarbonyl; R² represents hydrogen or(C₁-C₈)-alkyl; R³ represents COOR¹⁵ or CONHR¹⁵; and e, g and h,independently of each other, represents integers from 0 to
 3. 3.5-membered ring heterocycle of the formula I according to claim 1 inwhich W represents R¹-A—CH═C in which A represents a phenylene radical,or W represents R¹-A—C(R¹³) in which A represents a methylene, ethylene,trimethylene, tetramethylene, cyclohexylene, phenylene orphenylene-methyl divalent radical; B represents a methylene, ethylene,trimethylene, tetramethylene, vinylene, or phenylene divalent radical; Edenotes R¹⁰CO; R and R⁰ denote, independently of each other, hydrogen or(C₁-C₆) -alkyl; R¹ represents X—NH—C(═NH), X—NH—C(═NX)-NH or X—NH—CH₂; Xrepresents hydrogen (C₁-C₆)-alkylcarbonyl, (C₁-C₆)-alkoxy-carbonyl,(C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxycarbonyl or(C₆-C₁₄)-aryl-C(₁-C₆)-alkoxycarbonyl; R² represents hydrogen or(C₁-C₈)-alkyl; R³ represents CONHR¹⁵; R¹⁵ represents R¹⁶-(C₁-C₆)-alkylor R¹⁶, where R¹⁶ represents a 7-to 12-membered bridged bicyclic ortricyclic radical which is saturated or partially unsaturated and whichcontains from zero to four identical or different heteroatoms from thegroup nitrogen, oxygen and sulphur and which is unsubstituted orsubstituted by one or more identical or different sustituents from thegroup (C₁-C₄)-alkyl and oxo; and e, g and h, independently of eachother, represent integers from 0 to 3, and b, c and d represent
 1. 4.5-membered ring heterocycle of the formula I according to claim 1 inwhich, at the same time, W represents R¹-A—C(R¹³) Y represents acarbonyl group; Z represents N(R⁰); A represents a 1,4-phenyleneradical; B represents a methylene radical; D represents C(R²) (R³); Erepresents R¹⁰CO; R and R⁰, independently of each other, representhydrogen or (C₁-C₄)-alkyl R¹ represents H₂N—C(═NH), H₂N—C(—NH)═NH orH₂N—CH₂; R² represents hydrogen; R³ represents the radical CONHR¹⁵; R¹⁰represents hydroxyl or (C₁-C₈)-alkoxy; R¹³ represents (C₁-C₆)-alkyl,(C₅-C₇)-cycloalkyl or benzyl; R¹⁵ represents an adamantyl radical or anadamantylmethyl radical; b, c and d represent 1, e, f and g represent 0,and h represents 1 or
 2. 5. Pharmaceutical preparation, characterized inthat it contains one or more compounds of the formula I according toclaim 1 or one or more physiologically tolerated salts thereof, asactive compound together with pharmaceutically acceptable excipients andadditives.
 6. Process for preparing a compound of the formula Iaccording to claim 1, by the condensation of a compound of the formulaII

with a compound of the formula III

in which W, Y, Z, B, D, E and R, and also b, d, e, f, g and h, aredefined as indicated in claim 1, and G represents hydroxycarbonyl,(C₁-C₆)-alkoxycarbonyl, carboxylic acid chlorides, esters or anhydrides,or represents isocyanato.
 7. Process for the treatment of a host in needthereof comprising administering an effective dose of a compound of theformula I according to claim 1 and/or of its physiologically toleratedsalts, as inhibitors of thrombocyte aggregation, of the metastasizationof carcinoma cells, and also of the binding of osteoclasts to the bonesurface.
 8. Process for producing a pharmaceutical preparation,containing one or more compounds of the formula I according to claim 1,or one or more physiologically tolerated salts thereof, characterized bymixing them together with pharmaceutically acceptable excipients andadditives and, optionally, one or more different pharmacological activecompounds acceptable excipients and additives and, optionally, one ormore different pharmacological active compounds to produce a preparationsuitable for administration.
 9. 5-Membered ring heterocycles of thegeneral formula I according to claim 1 in which W representsR¹-A—C(R¹³), and R¹³ represents (C₁-C₆)-alkyl,(C₆-C₁₄)aryl-(C₁-C₈)-alkyl which is optionally substituted in the arylradical, or (C₃-C₈)-cycloalkyl.
 10. 5-Membered ring heterocycleaccording to claim 4 in which R¹³ represents methyl.
 11. 5-Membered ringheterocycle according to claim 3 in which R¹⁵ represents an adamantyl oradamantylmethyl radical.
 12. 5-Membered ring heterocycle according toclaim 4 in which R and R⁰ represent hydrogen, methyl or ethyl, R¹⁰represents hydroxyl or (C₁-C₄)-alkoxy, R¹³ represents methyl, and hrepresents
 1. 13.(2-((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)-L-aspartyl-1-adamantylamide, or a physiologically tolerated saltthereof. 14.(2-((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)-L-aspartyl-2-adamantylamide, or a physiologically tolerated saltthereof.
 15. (2-((R,S)-4-(4-(Aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl)-L-aspartyl-(1-adamantylmethyl) amide,or a physiologically tolerated salt thereof.